>467p  1919 

If  ORNIA     SAN   DIEGO  B 


3   1822  01222  2360 


LI3RA&Y 

UNJVEPSITY  OF 
CALfFORMJA 
SAN  UtEOQ 


A 


BM 


IKttERSlTY  OF  CALIFORNIA,  SAN  DIEW 
W  iOUA.  CAUFOftNIA 


6I0MEDICAI  UBRARY 
•INIWRSTV  DATE  DUE   S»H  WER. 

1         '    .  ''  -'' 

NOV  % 

1  RFP'n 

91 V  V    w 

-  .  •  .  -. 

A 

JAN  1 

7  REC'D 

GAVLORD 

PRINTED  IN  US* 

WO  2??  S467p  1919 

'iNlVI  RSITY  OF  CALK  01 


3   1822  01222  2360 


\aID 


\ 


THE  PRINCIPLES  OF  ACIDOSIS 

AND  CLINICAL  METHODS 

FOR  ITS  STUDY 


BY 
ANDREW  WATSON  SELL ARDS 

ASSOCIATE  IN  HARVARD  MEDICAL  SCHOOL 
DEPARTMENT  OF  TROPICAL  MEDICINE 


CAMBRIDGE 

HARVARD  UNIVERSITY  PRESS 

1919 


COPYEIGHT,  1917 
HARVARD  UNIVERSITY  PRESS 

Issued  September  1917 
Reprinted  July  1919 


i* 


PREFATORY  NOTE 


The  development,  of  the  theory  of  acidosis  has  been  a 
gradual  and  complicated  process.  Now  that  the  subject 
is  beginning  to  take  definite  form,  it  has  seemed  advis- 
able to  analyze  the  more  important  and  representative 
articles.  Two  excellent  reviews  of  acidosis  have  ap- 
peared in  the  past,  one  by  Kraus  and  Honigmann  *  in 
1S95  and  another  by  Ewing  f  in  1908.  Since  this  time 
fundamental  advances  have  been  made. 

My  own  interest  in  the  subject  dates  from  the  study 
in  Manila  at  the  Philippine  Bureau  of  Science  of  acidosis 
in  the  nephritis  of  Asiatic  cholera.  This  was  followed  by 
an  investigation,  along  similar  lines,  of  various  nephrop- 
athies in  the  clinic  of  Professor  Lewellys  F.  Barker  in 
Baltimore.  The  interest  in  the  results  has  been  con- 
siderably enhanced  by  combining  the  study  of  the  sub- 
ject in  tropical  and  general  medicine;  unfortunately 
these  two  phases  of  internal  medicine  often  tend  to  de- 
velop along  separate  and  independent  lines. 

In  order  to  limit  the  size  of  this  volume,  complete 
evidence  is  not  quoted  for  the  statements  and  conclu- 
sions which  appear,  but  full  references  are  given  in  each 
instance  to  the  literature.  In  its  present  form  this  mon- 
ograph is  intended  to  cover  the  requirements  for  the 
routine  of  the  clinic  as  far  as  theory,  application  and 
technical  methods  are  concerned.  The  classical  ar- 
rangement as  regards  the  expected  sequence  of  definition, 

*  Kraus  u.  Honigmann.  Ergeb.  d.  allgem.  Path.  Morph.  u.  Physiol,  d. 
Menschen  u.  d.  Tiere,  1895. 

t  Ewing.    Arch.  Int.  Med.  1908,  II,  330  and  448. 


iv  PREFATORY  NOTE 

etiology,  diagnosis,  and  therapy  has  been  sacrificed 
completely  for  the  sake  of  simplicity  of  presentation. 

I  have  endeavored  to  condense  the  subject  as  fully  as 
is  consistent  with  a  comprehensive  presentation  and 
without  neglecting  to  point  out,  sometimes  in  detail, 
the  places  where  our  information  is  incomplete.  The 
apparently  unavoidable  length  is  a  source  of  much 
regret  to  me. 

I  take  this  occasion  to  express  my  indebtedness  to 
Dr.  Richard  P.  Strong,  Director  of  the  Harvard  School 
of  Tropical  Medicine.  It  also  gives  me  much  pleasure 
to  acknowledge  the  very  helpful  assistance  of  Dr.  David 
L.  Edsall,  Dr.  Otto  Folin,  Dr.  Thomas  R.  Boggs,  and 
Dr.  Francis  Peabody. 

To  Miss  Catherine  M.  Casassa,  the  Secretary  of  this 
School,  I  wish  to  make  grateful  acknowledgment  for 
her  efficient  and  conscientious  care  of  the  manuscript. 

Boston,  Massachusetts, 
May,  1917. 


y 


CONTENTS 


I.   Introduction 3 

Historical  Note.  Distinction  between  titration  values  and 
physicochemical  reaction.  Dissociation  and  association. 
Absence  of  acid  properties  in  dry  sulphuric  acid. 

II.  Equilibrium  between  Acids  and  Bases 9 

Methods  of  disposing  of  the  excess  of  the  acid  end-products 
of  a  normal  diet.  Oxidation  and  excretion.  Henderson's  fac- 
tor :  neutrality  regulation  by  the  phosphates,  carbonates  and 
proteins  of  the  serum.  Interception  of  ammonia.  Quantita- 
tive increase  of  these  processes  in  acidosis.  Importance  of 
fixed  bases  for  the  internal  respiration.  The  hypothetical 
condition  of  alkalosis. 

III.  Methods  of  Diagnosing  Acidosis 17 

Clinical  Signs.  Laboratory  methods.  Constancy  of  phys- 
icochemical reaction  of  blood  in  acidosis.  Confusion  con- 
cerning the  reaction  of  the  blood  in  pregnancy.  Behavior 
of  carbon  dioxide  and  ammonia.  Desirability  of  a  delicate 
and  pathognomonic  test  of  general  application. 

IV.  Behavior  of  the  Body  in  Health  and  in  Acidosis 

towards  Sodium  Bicarbonate 24 

The  testing  of  the  tolerance  to  bicarbonate.  Occurrence  of 
high  tolerance  in  various  nephropathies.  Interpretation  of 
this  tolerance.     Proof  that  it  represents  an  acidosis. 

V.  Relative  Value  of  the  Various  Tests  for  Acidosis  .  34 
Relative  delicacy  of  the  various  tests.  Precautions  to  be 
observed  in  interpretation  of  acetone,  carbon  dioxide  and 
ammonia.  Choice  of  tests  under  various  conditions;  the 
tests  employed  in  establishing  the  occurrence  of  acidosis  in 
certain  nephropathies. 

VI.   Definition  of  Acidosis 42 

An  impoverishment  of  the  body  in  fixed  bases.  Fallacy  of 
dividing  acidoses  into  relative  and  absolute  types  and  dif- 
ficulty of  distinguishing  compensated  and  uncompensated 
cases.  Selection  of  a  standard  test  for  detecting  systemic 
changes  in  the  alkali  reserve. 


vi  CONTENTS 

VII.   Occurrence  of  Acidosis 48 

Fatal  forms  in  diabetes  in  certain  nephropathies  and  some 
of  the  diseases  of  children.  Moderate  grades  of  acidosis  in 
other  conditions.  Tendency  to  exaggerate  the  frequency  of 
acidosis. 

VIII.  Therapy 53 

Mode  of  action  of  alkalies.  Beneficial  action  in  acute 
nephritis  of  Asiatic  cholera.  Consideration  of  chronic  ne- 
phritis. Lack  of  permanent  value  of  alkali  therapy  in  ad- 
vanced acidoses  and  some  possible  explanations. 

IX.  Differential  Diagnosis 69 

Differentiation  of  the  various  comas.  Constancy  of  acidosis 
in  uraemia  as  contrasted  with  cardiac  and  cerebral  con- 
ditions. 

X.  Etiology  of  Acidosis 73 

Disturbance  of  oxidation  in  diabetes  and  impaired  elimina- 
tion in  nephritis.  Fundamental  and  incidental  features  of 
acidosis.  Incomplete  knowledge  in  regard  to  the  ammonia 
metabolism.  Evidence  that  acidosis  in  nephritis  is  a  sec- 
ondary and  not  a  primary  factor. 

XI.  Resume 83 

XII.  Appendix.    Technique  of  Methods 95 

Bibliography 112 


THE  PRINCIPLES  OF  ACIDOSIS 

AND  CLINICAL  METHODS 

FOR  ITS  STUDY 


J 


■ 


INTRODUCTION 

The  phenomenon  of  acidosis  apparently  represents  one 
of  the  simpler  problems  in  biological  chemistry;  never- 
theless the  development  of  the  subject  has  been  very 
gradual  although  it  has  occupied  a  prominent  place  in 
the  field  of  internal  medicine  for  several  decades.  Nu- 
merous erroneous  conceptions  have  arisen  from  time  to 
time  and  these  are  being  eliminated  only  with  difficulty. 
The  theory  had  its  inception  in  1850  when  Bous- 
singault l  using  very  satisfactory  methods  made  the 
extremely  valuable  discovery  that  large  amounts  of  am- 
monia frequently  appear  in  the  urine  of  diabetic  pa- 
tients. As  pointed  out  by  Folin  2  it  was  not  until  1880 
that  Hallervorden  3  using  an  inferior  technique  repeated 
and  confirmed  Boussingault's  work.  Notwithstanding 
these  circumstances  the  work  is  usually  attributed  to 
Hallervorden.  The  search  for  acid  radicals  to  account 
for  the  presence  of  these  ammonium  salts  in  acid  urine 
culminated  in  1883  in  Stadelmann's  4  discovery  of  oxy- 
butyric  acid.  Confusing  theories  were  arising  at  this 
period  but  already  in  1877  Walter  5  had  clarified  the 
situation  considerably  by  demonstrating  in  animals  that 
the  ingestion  of  mineral  acids  proved  fatal  although  the 
blood  serum  remained  faintly  alkaline  to  litmus.  The 
first  definite  clinical  observations  were  made  during 
this  period  by  Kussmaul  6  who  noted  the  air  hunger  of 
advanced  diabetic  patients.  In  recent  years  there  has 
been  renewed  activity  in  the  study  of  acidosis,  partial- 


4  THE  PRINCIPLES  OF  ACIDOSIS 

larly  of  those  types  of  non-diabetic  origin.  These  in- 
vestigations have  served  to  emphasize  that  the  fixed 
alkalies  are  necessary  for  the  physiological  requirements 
of  the  body  and  that  they  are  essential  to  life. 

In  considering  the  requisite  constituents  of  a  balanced 
diet  attention  is  not  ordinarily  directed  toward  the 
alkalies  since  this  component  usually  regulates  itself 
automatically.  However,  it  is  only  by  careful  regula- 
tion and  conservation  that  a  sufficient  supply  is  main- 
tained in  the  body  to  meet  the  normal  physiological 
requirements  of  metabolism.  With  an  ordinary  mixed 
diet  there  is  a  tendency  toward  a  constant  production 
of  acid  radicals,  but  these  radicals  are  prevented  from 
appearing  as  free  acid  in  the  blood  or  other  tissues 
chiefly  by  two  processes,  namely,  excretion  and  neutral- 
ization. In  an  exactly  similar  manner,  i.  e.,  by  excretion 
and  neutralization,  the  body  also  provides  against  the 
accumulation  of  excessive  amounts  of  alkali.  Upon 
closer  examination  it  will  be  seen  that,  bv  means  of  a 
delicately  balanced  mechanism,  the  equilibrium  be- 
tween acids  and  bases  is  maintained  at  a  remarkably 
constant  level.  The  maintenance  of  this  equilibrium  is 
of  fundamental  importance  inasmuch  as  a  nice  adjust- 
ment of  the  reaction  of  the  various  fluids  and  tissues  is 
important  for  many  of  the  processes  taking  place  in  the 
body.  Henderson  7  has  emphasized  that  the  constancy 
of  the  reaction  of  the  blood  is  even  more  carefully 
guarded  than  the  other  great  constants  of  the  body 
such  as  temperature  and  osmotic  pressure. 

Before  discussing  the  mechanism  by  which  this  equi- 
librium is  controlled,  it  will  be  well  to  review  briefly  a 
few  preliminary  considerations  regarding  acids  and 
bases  and  the  reactions  of  solutions.   In  the  first  place, 


INTRODUCTION  5 

one  must  not  lose  sight  of  the  fact  that  many  neutral 
or  practically  neutral  substances  may  be  capable  of 
maintaining  their  neutrality  even  after  the  addition  of 
free  acid  or  base;    consequently  one  does  not  require 
even  a  weak  base  to  neutralize  a  strong  acid.    One  of 
the  simplest  examples  of  this  is  the  neutralization  of 
hydrochloric  acid  by  a  suspension  of  neutral  calcium 
carbonate.    A  more  interesting  illustration  is  afforded 
by  blood  serum,  which,  though  only  very  slightly  alka- 
line can,  by  virtue  of  its  carbonates,  phosphates  and 
proteins,  neutralize  moderate  amounts  of  acid.     This 
ability  to  neutralize  acid  or  base  may  conveniently  be 
termed  "  titratable  reaction  "  in  distinction  from  the 
actual  reaction.    The  true  reaction  of  a  fluid  concerns 
itself  only  with  that  portion  of  acid  or  base  which,  after 
going  into  solution,  becomes  dissociated  into  hydro- 
gen and  hydroxyl  ions.   The  absolute  dependence  of  the 
reaction  upon  the  splitting  up  of  an  acid  or  alkali  into  its 
ions  may  be  emphasized  by  considering  the  opposite  of 
dissociation,  namely,  association.    In  contrast  for  ex- 
ample to  the  complete  dissociation  at  infinite  dilution, 
an  acid  is  completely  associated  when  it  is  anhydrous. 
Thus  chemically  pure  and  absolutely  water  free  sul- 
phuric acid  does  not  possess  any  of  the  ordinary  proper- 
ties of  an  acid.     Blue  litmus  and  the  ordinary  metals 
such  as  sodium,  if  actually  dry,  remain  entirely  un- 
affected by  it.    There  are  other  striking  examples  illus- 
trating the  importance  of  the  presence  of  water.  Sulphur 
and  phosphorus  will  not  burn  in  dry  oxygen.     Hydro- 
chloric acid  if  dry  will  react  neither  with  dry  carbonates 
nor  even  with  dry  ammonia.8 

The  dissociation  which  occurs  in  ordinary  solutions  is 
usually  measured  by  physicochemical  methods  and  in 


6  THE  PRINCIPLES  OF  ACIDOSIS 

order  to  avoid  any  possible  confusion  it  is  often  con- 
venient to  use  the  expression  "  physicochemical  re- 
action "  though  obviously  a  solution  cannot  have  more 
than  one  reaction. 

The  titration  value  of  a  solution  is,  necessarily,  a 
broader  term  than  reaction,  since  it  includes  not  only 
the  free  hydrogen  and  hydroxyl  ions  present,  but  all  the 
reserve  of  undissolved  and  undissociated  hydrogen  or 
hydroxyl  which  can  be  liberated  as  ions.  Even  in 
the  case  of  a  mineral  acid  dissolved  in  water,  the  titra- 
tion value  is  greater  than  the  actual  reaction  except  at  a 
dilution  of  infinity,  since  for  all  dissociated  hydrogen 
ions  there  is  invariably  a  definite  and  fixed  amount 
of  undissociated  hydrogen  that  will  dissociate  upon 
neutralization  of  the  free  hydrogen  ions. 

Some  slight  confusion  has  arisen  from  the  fact  that 
certain  substances  though  virtually  neutral  when  tested 
electrometrically,  nevertheless  give  a  distinctly  acid  or 
alkaline  reaction  with  ordinary  standard  indicators. 
This  somewhat  perplexing  situation  is  readily  under- 
stood when  it  is  remembered  that  these  indicators 
themselves  are  either  weak  acids  or  bases  and  are  capa- 
ble of  changing  slightly  the  ionization  of  the  fluids  to 
which  they  are  added.  The  error  lies  in  the  assumption 
that  these  indicators  are  neutral;  moreover  the  ordinary 
indicators  vary  greatly  among  themselves  as  regards 
the  amount  of  hydrogen  or  hydroxyl  ions  that  is  re- 
quired to  overcome  their  own  reaction  and  produce  a 
change  in  color. 

The  theoretical  consideration  on  which  this  discussion 
rests  is  illustrated  in  the  accompanying  outline  showing 
the  behavior  of  various  substances  toward  indicators 
and  acids  under  different  conditions. 


INTRODUCTION 


THE  REACTION  AND  TITRATION  VALUES  OF  VARIOUS 

SUBSTANCES 


Substances 

under 
examination 

Reaction 
(physico- 
chemical) 

Behavior 

with 
indicators 

Effect  of  moder- 
ate addition  of 
acid 

Titration 
value 

Distilled  water 

Neutral 

Neutral 

Becomes  acid 

None 

Suspension  of 
CaC03in  water 

Neutral 

Neutral 

Remains  neu- 
tral 

High 

Blood  serum 

Faintly  al- 
kaline 

Distinctly  al- 
kaline to  lit- 
mus, methyl 
orange,  etc.; 
acid  to  phen- 
olphthalein 

Alkaline,  neu- 
tral or  acid  * 

Moderate 

Anhydrous 
H2S04 

Neutral 

Neutral  f 

.... 

High 

H2SO4  at  high 
dilution 

Acid 

Acid 

Practically 
equivalent  to 
physicochem- 
ical  reaction 

*  According  to  amount  added. 


t  Under  anhydrous  conditions. 


In  speaking  of  the  physicochemical  reaction  of  a  solu- 
tion, even  in  case  of  the  faintly  alkaline  blood  serum,  it 
must  be  emphasized  that  an  increase  in  the  hydrogen 
ion  concentration  does  not  by  any  means  imply  that 
the  solution  has  become  acid.  This  becomes  self- 
evident  when  we  remember  that  the  reaction  can  be 
stated  equally  well  in  terms  of  the  hydroxyl  ion  concen- 
tration. The  mere  presence  of  hydrogen  ions  does  not 
indicate,  in  any  way,  whether  the  solution  is  acid  or 
alkaline,  since  even  in  the  strongest  solutions  of  acid 


8  THE  PRINCIPLES  OF  ACIDOSIS 

and  alkali,  both  hydrogen  and  hydroxyl  ions  are  con- 
stantly present,  a  definite  equilibrium  existing  between 
the  two.  Thus  if  a  ten  per  cent  solution  of  caustic  soda 
is  reduced  to  a  strength  of  five  per  cent  by  neutraliza- 
tion or  by  dilution  then  there  has  been  a  marked  in- 
crease in  its  hydrogen  ion  concentration  though  the 
solution  remains  strongly  alkaline.  This  principle  is 
not  infrequently  overlooked  in  the  interpretation  of 
the  data  obtained  on  blood  serum  even  by  workers  in 
this  field. 


II 

EQUILIBRIUM  BETWEEN  ACIDS  AND   BASES 

Normal  Conditions.  The  highly  important  procedure 
of  disposing  of  the  excess  of  acid  radicals  arising  in  me- 
tabolism and  of  maintaining  a  constant  reaction  of  the 
blood  is  accomplished  by  a  mechanism  which  is  ex- 
tremely efficient  and  also  comparatively  simple.  More- 
over, this  mechanism  is  in  active  operation  in  health  as 
well  as  in  acidosis.  Even  in  an  omnivorous  diet  the 
acid  radicals  arising  from  the  combustion  of  sulphur, 
phosphorus  and  carbon  exceed  the  bases  which  are 
present.  This  excess  of  acid  is  corrected  not  by  any 
spontaneous  or  artificial  change  in  the  diet  but  by  the 
processes  of  oxidation,  excretion  and  neutralization. 
The  handling  of  the  carbon  is  a  relatively  simple  prob- 
lem, since  it  is  readily  oxidized,  the  resulting  carbon 
dioxide  being  eliminated  by  the  lungs  as  such  and  by  the 
kidneys  after  conversion  to  urea.  A  limited  amount  of 
the  acids  arising  from  the  sulphur  and  phosphorus  are 
neutralized  by  the  fixed  bases  of  the  body.  The  striking 
feature,  however,  consists  in  the  ability  of  the  kidney 
to  excrete  a  sharply  acid  urine  from  a  slightly  alkaline 
blood  plasma.  But  alkalies  can  also  be  eliminated 
equally  well.  Thus  the  kidney  regulates  the  composi- 
tion of  the  blood  in  its  finer  details,  excreting  the  acid 
or  alkaline  phosphates  and  carbonates  according  as  con- 
ditions may  require.  Henderson  9  has  pointed  out  and 
established  that  the  mono-  and  di-sodium  phosphates 
and  carbonates  of  the  blood  constitute  one  of  the  fun- 


10  THE  PRINCIPLES  OF  ACIDOSIS 

damental  features  in  the  regulation  of  neutrality,  since 
the  mono-sodium  salt  (NaH2P04)  is  acid  and  the  di- 
sodium  salt  (Na2HP04)  is  alkaline  to  litmus.  It  might 
appear  at  first  glance  that  a  mixture  of  these  phosphates 
in  aqueous  solution  would  react  readily  with  acid  or 
alkali  with  a  corresponding  change  in  the  reaction  of 
the  solution.  On  the  contrary,  although  chemical  com- 
bination takes  place,  the  reaction  does  not  change  until 
after  the  addition  of  considerable  amounts  of  acid  or 
alkali,  since  a  readjustment  of  the  proportions  of  mono- 
and  di-basic  phosphates  occurs.  The  normal  carbonate 
and  bicarbonate  of  the  serum  act  in  a  similar  though 
somewhat  less  effective  manner.  Henderson  has  em- 
phasized that  this  mixture  of  phosphates  and  carbon- 
ates is  the  most  effective  which  could  be  devised  for 
maintaining  a  constant  reaction;  it  is  extremely  efficient 
not  only  in  aqueous  solution  but  in  the  presence  of 
colloids,  such  as  serum  affords,  its  value  is  distinctly 
enhanced.  The  colloids  by  their  amphoteric  nature 
are  able  to  take  up  very  appreciable  amounts  of  acid 
or  base  without  changing  their  reaction.  But  this  re- 
markable stability  of  the  blood  even  in  cooperation 
with  the  kidney  is  not  sufficient  to  care  for  the  excess 
of  phosphoric  and  other  acid  end-products  under  normal 
conditions.  A  third  very  important  step  consists  in 
securing  another  source  of  alkali  in  addition  to  that 
which  occurs  in  the  food.  This  is  accomplished  in  the 
course  of  the  metabolism  of  nitrogen  through  the  inter- 
ception and  neutralization  of  ammonia  by  the  acid 
radicals.  It  is  generally  accepted  that,  for  all  practical 
purposes,  ammonia  occurs  in  the  urine  physiologically 
only  to  the  extent  which  it  is  needed  for  the  neutrali- 
zation of  acid,  the  remainder  of  the  ammonia  being 


ACIDS  AND  BASES  11 

promptly  converted  to  urea.  The  evidence  for  this  view 
consists  chiefly  in  the  fact  that  in  normal  individuals 
the  feeding  of  sodium  bicarbonate  causes  a  prompt  fall 
in  the  ammonia  output  in  the  urine.  Indeed,  there  is 
only  a  negligible  residuum  of  ammonia  (about  one- 
half  per  cent  of  the  total  urinary  nitrogen)  which  can- 
not be  replaced  by  feeding  alkali.10 

In  summarizing  the  mechanism  of  the  normal  equilib- 
rium betHveen  acids  and  bases  as  it  occurs  in  health, 
we  have  on  the  one  hand  a  liberal  production  of  acids 
arising  in  the  main  from  the  combustion  of  carbon, 
phosphorus  and  sulphur.  Nevertheless,  a  slightly  alka- 
line reaction  of  the  blood  is  constantly  maintained, 
primarily  by  the  following  means: 

1.  Intake  of  fixed  bases  in  the  food. 

2.  Elimination 

(a)  of  carbon  dioxide  by  the  lungs, 

(b)  of  acid  by  the  kidney. 

3.  Neutralization  of  acid  in  the  body  by  ammonia. 
In  the  metabolism  of  acids,  it  is  seen  that  one  of  the 

extremely  important  factors  is  the  process  of  oxidation. 
By  this  means,  the  organic  acid  radicals  are  practically 
destroyed  being  burned  to  carbon  dioxide;  at  the  same 
time  considerable  quantities  of  mineral  acids  are  pro- 
duced from  the  proteins  and  these  cannot  be  oxidized 
further.  In  either  case  after  the  preliminary  step  of 
oxidation,  the  end-products  are  disposed  of  by  two  gen- 
eral processes,  namely,  (1)  excretion  and  (2)  neutrali- 
zation. 

Pathological  Conditions.  The  maintenance  of  a  proper 
reaction  of  the  blood,  although  a  very  simple  matter  in 
health,  may  even  with  extensive  artificial  aid  become 
a  difficult  problem  in  disease.    The  measures  for  thera- 


12  THE  PRINCIPLES  OF  ACIDOSIS 

peutic  purposes  will  be  discussed  subsequently  and  it  is 
necessary  to  consider  here  only  those  means  by  which 
the  body  spontaneously  protects  itself  against  an  ac- 
cumulation of  acid.  This  protection  is  accomplished 
in  fundamentally  the  same  manner  in  health  and  in 
disease.  In  the  latter  case,  even  under  extreme  con- 
ditions, the  body  responds  not  by  the  development  of 
a  new  method  for  the  disposal  of  acids  but  by  a  quanti- 
tative increase  in  its  normal  processes.  Certain  features, 
however,  which  are  not  conspicuous  under  normal  con- 
ditions become  more  prominent  under  the  tension  of 
the  state  of  acidosis  and  the  increase  in  the  normal 
compensatory  processes  is  not  altogether  evenly  dis- 
tributed among  the  various  factors.  Considering  first 
the  excretory  processes,  the  elimination  of  carbon  diox- 
ide is  readily  accomplished  as  long  as  fixed  bases  are 
available  to  permit  of  its  transportation  to  the  lungs. 
In  the  case  of  the  kidney,  however,  the  margin  of  safety 
is  small  indeed  since  the  amount  of  organic  or  mineral 
acids  which  it  can  excrete  is  not  very  significant  in 
comparison  to  the  quantities  which  sometimes  must  be 
disposed  of  in  acidosis.  If  excessive  amounts  tend  to 
accumulate  or  if  the  kidney  is  damaged,  then  other 
methods  must  be  found  for  disposing  of  this  excess. 
There  is  a  certain  reserve  of  fixed  alkali  which  can  be 
drawn  upon  to  a  limited  extent  without  disturbing  the 
body  metabolism.  This  source  of  supply  is  not  large 
and  under  certain  conditions,  especially  in  diabetes, 
the  bulk  of  the  increased  work  falls  upon  the  process  of 
neutralization  by  ammonia.  Fortunately  there  is  a 
large  excess  of  nitrogen  from  the  catabolism  of  proteins 
which  is  available  for  this  purpose;  under  normal  con- 
ditions only  a  small  fraction  of  the  total  nitrogen  of  the 


ACIDS  AND  BASES  13 

urine  (about  two  to  five  per  cent)  is  utilized  for  the 
neutralization  of  acids.  In  acidosis  proportionately 
much  more  (ten  to  forty  per  cent)  of  this  nitrogen  is 
intercepted  by  acid.  Notwithstanding  this  remarkable 
increase  in  the  ammonia  output  and  the  efficiency  of 
Henderson's  factor  as  regards  the  composition  of  the 
blood,  the  fixed  bases  gradually  become  depleted.  The 
efficiency  of  the  compensatory  processes  is  determined 
not  by  the  height  of  the  ammonia  coefficient,  but  the 
crucial  test  of  these  processes  consists  in  their  ability 
to  protect  and  conserve  the  supply  of  fixed  bases  or 
base  yielding  substances  in  the  blood  and  other  tissues. 
The  necessity  of  avoiding  a  marked  acidosis  is  evi- 
dent when  we  consider  the  importance  of  these  bases  in 
metabolism.  Normally  oxygen  is  carried  by  the  arterial 
blood  from  the  lungs  to  the  tissues  where  the  carbon  is 
burned  and  the  resulting  carbon  dioxide  is  carried  as 
carbonate,  largely  sodium  bicarbonate,  by  the  venous 
blood  to  the  lungs,  where  the  bicarbonate  breaks  up, 
the  carbon  dioxide  is  exhaled,  the  normal  carbonate 
returning  by  the  arterial  blood  to  the  tissues  to  take  up 
and  carry  away  more  carbon  dioxide.  With  the  deple- 
tion of  the  carbonates,  the  oxygen  is  still  carried  by  the 
arterial  blood  but  the  resulting  carbon  dioxide  gradually 
accumulates  in  the  tissues,  since  there  is  not  an  ade- 
quate supply  of  bases  for  transporting  it  to  the  lungs. 
With  this  accumulation  of  carbon  dioxide,  the  tissues 
are  no  longer  able  to  utilize  the  oxygen  brought  to 
them;  *  the  individual  becomes  dyspnoeic  and  suffers 
from  subjective  symptoms  of  suffocation  just  as  though 
he  were  deprived  of  air.     The  oxygen,  since  it  cannot 

*  This  is  the  usual  explanation  though  the  evidence  in  support  of  it  is 
not  altogether  complete. 


14  THE  PRINCIPLES  OF  ACIDOSIS 

be  taken  up  by  the  tissues,  remains  in  the  venous  blood, 
giving  it  an  arterial  color,  the  blood  in  the  veins  ordi- 
narily being  dark  simply  by  reason  of  the  withdrawal 
of  oxygen,  rather  than  on  account  of  the  presence  of 
carbon  dioxide.  This  exhaustion  of  carbonates  leads 
first  to  the  development  of  air  hunger  and  eventually 
to  death  if  the  exhaustion  is  sufficiently  extreme.  The 
cardinal  feature  of  acidosis  is,  that  there  is  neither  an 
increased  production  nor  an  accumulation  of  acid  in 
the  body,  but  the  reserve  supply  of  alkali  yielding  sub- 
stances is  depleted  in  the  prevention  of  the  appearance 
of  acid  in  the  blood. 

In  contrast  to  acidosis,  it  may  be  well  to  consider 
briefly  the  hypothetical  possibility  of  the  so-called 
"  alkalosis."  Experimentally,  it  is  of  course  a  simple 
matter  to  kill  animals  with  massive  injections  of  alkali. 
However,  under  conditions  that  arise  spontaneously  in 
man  or  lower  animals,  there  is  no  evidence  that  exces- 
sive amounts  of  alkali  can  accumulate  in  the  body. 
Such  an  excess  is  readily  avoided,  by  a  reduction  in  the 
amount  of  ammonia  which  is  intercepted  for  the  neu- 
tralization of  acids,  and  by  the  excretion  of  alkali  by  the 
kidney.  In  some  recent  papers,  Wilson  u  and  his  col- 
laborators have  brought  forth  some  highly  interesting 
facts  on  the  ameliorating  effect  of  acidosis  upon  para- 
thyroid tetany.  These  authors  find  that  periods  of 
alkalosis  develop  spontaneously  before  an  attack  of 
tetany  and  are  succeeded  by  periods  of  acidosis  during 
or  after  the  attack.  Also,  beneficial  results  were  ob- 
tained by  the  administration  of  acid.  According  to 
these  findings,  the  removal  of  the  parathyroids  produces 
a  state  of  alkalosis  which  is  responsible,  in  part,  for  the 
development  of  tetany;   if  this  alkalosis  is  corrected  or 


ACIDS  AND  BASES  15 

over  corrected,  spontaneously  or  by  the  administration 
of  acid,  then  the  tetany  is  relieved.  Alkalosis,  then,  as 
designated  by  Wilson  consists  in  an  increase  in  the  basic 
radicals  of  the  blood;  this  increase  may  be  absolute  or 
there  may  be  a  decrease  in  the  production  of  acid  radi- 
cals (except  carbon  dioxide)  resulting  in  a  relative  excess 
of  basic  radicals.  In  either  case  the  resulting  physi- 
cochemical  reaction  of  the  blood  may  remain  unchanged. 
While  these  facts  bearing  upon  the  relief  of  parathyroid 
tetany  are  highly  important,  the  interpretation  of  them 
on  the  basis  of  an  alkalosis  is  not  adequately  supported 
by  the  experimental  data.  The  evidence  of  the  exist- 
ence of  acidosis  consisted  in  the  determination  of  (1)  the 
dissociation  constant  of  oxyhaemoglobin,  (2)  the  carbon 
dioxide  content  of  the  alveolar  air,  (3)  the  hydrogen 
ion  concentration  of  the  blood,  (4)  the  ammonia  output 
in  the  urine,  (5)  the  hydrogen  ion  concentration  and 
total  acidity  of  the  urine.  Unfortunately  it  is  neces- 
sary to  emphasize  that  one  of  the  technical  methods 
employed  was  at  fault,  namely,  the  reaction  to  indica- 
tors of  the  dialysate  from  blood  serum  does  not  repre- 
sent the  hydrogen  ion  concentration  of  the  blood.  The 
examination  of  the  reaction  of  the  urine  is  of  importance 
on  account  of  its  bearing  upon  alkalosis.  A  diminution 
in  acidity  was  frequently  found  but  nevertheless  there 
was,  almost  constantly,  a  distinct  preponderance  of 
acid  radicals,  considerable  acid  and  ammonia  being 
excreted  in  the  urine.  In  exceptional  instances  an  alka- 
line urine  was  obtained.  In  the  presence  of  definite 
amounts  of  ammonium  salts,  such  a  reaction  is  without 
significance  in  the  absence  of  chemical  or  bacteriological 
data  to  determine  whether  this  alkalinity  was  due  to 
fixed  bases  or  to  ammonium  hydroxide.    Moreover,  the 


16  THE  PRINCIPLES  OF  ACIDOSIS 

occasional  voiding  of  an  alkaline  specimen  of  urine 
would  not  be  conclusive  proof  of  alkalosis,  even  though 
the  alkalinity  be  due  to  fixed  bases.  This  interesting 
fluctuation  in  the  excretion  of  acid  after  parathyroid- 
ectomy does  not  establish  that  there  was  a  preponder- 
ance of  the  basic  radicals  over  the  acid  end-products  or 
that  there  was  an  increase  in  the  reserve  supply  of  alkali 
in  the  body. 

In  considering  the  hypothetical  possibility  of  an 
absolute  excess  of  fixed  bases  in  the  body,  it  is  difficult 
to  see  from  what  source  these  bases  could  be  obtained 
other  than  the  limited  amount  occurring  in  the  food 
supply  or  how  they  could  escape  excretion  by  the  kidney 
or  neutralization  by  acids.  The  protein  metabolism 
yields  a  large  supply  of  acids  which  is  readily  avail- 
able for  the  neutralization  of  bases;  even  the  excessive 
amounts  of  ammonia,  such  as  occur  in  acute  yellow 
atrophy,  do  not  by  any  means  exhaust  the  supply  of 
acid  radicals.  In  a  search  for  the  condition  of  alkalosis 
one  should  be  cautious  about  interpreting  an  increase 
in  the  carbon  dioxide  content  of  the  alveolar  air  as  indi- 
cating an  increase  in  the  carbonates  of  the  blood.  It 
may  mean  simply  that  an  unusually  large  proportion  of 
the  normal  carbonate  is  converted  in  the  lungs  to  bicar- 
bonate, i.  e.,  that  there  is  a  change  in  the  relative  pro- 
portion of  the  two  salts  without  a  change  in  the  total 
quantity.  The  occurrence  of  alkalosis,  in  the  sense  of 
a  relative  or  absolute  excess  of  alkali  reserve  over  the 
normal,  in  the  blood  and  body  tissues,  has  not  been 
established;  on  a  priori  grounds,  it  is  difficult  to  con- 
ceive that  the  protein  metabolism  in  normal  or  patho- 
logical conditions  could  diminish  spontaneously  to  the 
point  where  an  alkalosis  would  prevail. 


Ill 

METHODS  OF  DIAGNOSING  ACIDOSIS 

Clinical  Signs.  The  state  of  acidosis  is  accompanied 
by  certain  clinical  manifestations  one  of  which  is  very 
characteristic.  In  advanced  cases,  the  respiration  be- 
comes moderately  rapid;  the  striking  feature  in  un- 
complicated cases  is  not  the  increase  in  rate  but  the 
pronounced  increase  in  depth  with  a  somewhat  pro- 
longed expiration.  This  dyspnoea  is  accompanied  not 
by  cyanosis  but  by  a  bright  color,  even  at  times  an 
abnormally  bright  color,  of  the  mucous  membranes. 
Physical  examination  of  the  chest  shows  nothing  to 
account  for  this  labored  respiration.  Such  a  picture 
constitutes  a  typical  air  hunger  and  is  a  very  character- 
istic symptom  provided  that  no  complicating  factors 
are  present.  It  occurs,  however,  only  in  advanced 
stages  of  acidosis. 

Laboratory  Methods.  For  the  detection  of  the  earlier 
stages,  a  fruity  odor  of  the  breath  is  of  course  very  help- 
ful in  diagnosing  diabetic  acidosis  but  it  is  preferable 
to  consider  here  only  the  general  methods  applicable  to 
all  types.  A  variety  of  laboratory  methods  are  avail- 
able.    These  may  be  conveniently  listed  as  follows: 

I.   Examination  of  the  blood  for 

1.  lowering  of  alkalinity, 

2.  lowering  of  carbon  dioxide  content. 

II.   Examination   of   respiration   for    lowering   of 
carbon  dioxide  tension  in  alveolar  air. 

17 


18  THE  PRINCIPLES  OF  ACIDOSIS 

III.   Examination  of  urine  for 

1.  excess  of  acid  or  for  abnormal  acids, 

2.  change  in  fixed  bases, 

3.  increase  in  ammonia  output. 

Of  this  list  it  is  obviously  desirable  to  select  some 
clinical  method  which  shall  be  firstly,  sufficiently  deli- 
cate to  detect  the  early  grades,  and  secondly,  shall  be 
applicable  to  all  types  regardless  of  etiology  and  in  the 
third  place  shall  be  pathognomonic  of  acidosis. 

In  the  examination  of  the  blood,  titration  methods 
for  changes  in  alkalinity  are  notoriously  inadequate. 
The  proteins  of  the  serum  interfere  seriously  with  the 
end  point  and  the  measurement  involves  comparatively 
slight  changes.  The  results  of  the  titration  methods  are 
at  best  only  suggestive,  even  in  outspoken  acidosis,  and 
are  without  value  in  early  cases.  In  contrast  to  the 
titratable  alkalinity  one  can,  with  sufficiently  elaborate 
equipment,  determine  accurately  the  physiocochemical 
reaction  of  the  blood.  It  has  finally  been  demonstrated, 
however,  that  this  determination  is  without  clinical 
interest.  This  result  was  predicted  by  Folin  2  when  the 
physiocochemical  methods  were  introduced  into  biology 
and  at  a  time  when  there  was  a  tendency  to  begin  to 
look  upon  the  titration  values  of  fluids  as  being  without 
biological  significance.  It  was  first  shown  by  Benedict 12 
in  1906  that,  by  virtue  of  the  compensatory  processes  of 
the  body,  the  reaction  of  the  blood  remains  practically 
constant  even  in  outspoken  acidosis.  It  is  only  in  the 
terminal  stages  of  a  fatal  case  that  a  demonstrable  in- 
crease takes  place  in  the  hydrogen  ion  concentration  of 
the  blood  and  even  then  it  is  measurable  only  with  deli- 
cate equipment.  This  result  has  been  confirmed  by  a 
number  of  observers  but  more  especially  in  this  country 


METHODS  OF  DIAGNOSING  ACIDOSIS       19 

by  Peabody.27  In  a  sense,  it  is  perhaps  more  nearly 
true  to  say  that  the  hydrogen  ion  eoncentration  of  the 
blood  remains  constant  even  in  fatal  acidosis  than  to 
give  the  impression  that  a  significant  increase  occurs. 
So  delicate  have  the  scientific  measurements  become 
that  changes  in  electrical  conductivity  can  be  detected 
which  approach  the  vanishing  point.  Thus  of  the  trust- 
worthy observations,  the  maximal  change  of  the  hydro- 
gen ion  concentration  in  fatal  acidosis  has  been  reported 
by  Peabody.  In  the  most  extreme  instance  the  decrease 
in  alkalinity,  as  compared  with  the  average  normal,  was 
equivalent  to  a  solution  about  five  hundred-millionths 
normal.     (0.000,000,056  for  PH  7.45  and  7.04.) 

Occasionally  work  is  reported  which  is  interpreted  as 
indicating  that  the  hydrogen  ion  concentration  changes 
rather  easily  even  in  mild  degrees  of  acidosis.  The  re- 
sults of  Hasselbalch  and  Gammeltoft 13  have  been 
sometimes  quoted  in  support  of  this  idea.  These 
authors  investigated  the  reaction  of  the  blood  during 
pregnancy.  From  the  estimation  of  the  ammonia  in  the 
urine  and  the  carbon  dioxide  of  the  alveolar  air  they 
concluded  that  a  very  slight  degree  of  acidosis  occurs 
late  in  pregnancy.  In  12  cases,  the  physicochemical  re- 
action of  the  blood  was  entirely  within  normal  limits 
except  for  an  occasional  isolated  analysis  in  one  or  two 
cases  showing  an  insignificant  increase  in  the  hydrogen 
ion  concentration  not  definitely  beyond  the  limits  of 
error.  In  contrast  to  these  results  Michaelis,66a  in  the 
study  of  a  series  of  23  cases  of  pregnancy,  found  an 
extremely  slight  decrease  in  the  hydrogen  ion  concen- 
tration; this  author  felt  that  the  changes  were  appar- 
ently slightly  greater  than  the  limits  of  error  of  his 
method.    A  very  striking  divergence  from  this  view  of 


20  THE  PRINCIPLES  OF  ACIDOSIS 

the  constancy  of  the  physicochemical  reaction  of  the 
blood  has  been  reported  by  Rowntree.14  The  results 
are  based  upon  the  behavior  to  indicators  of  the  dialy- 
sate  from  blood  serum.  In  marked  contrast  to  the  ad- 
vanced cases  of  acidosis  showing  only  slight  changes 
even  at  death,  Rowntree  reports  rather  wide  fluctua- 
tions in  the  hydrogen  ion  concentration;  moreover 
these  occasionally  occurred  in  conditions  in  which  there 
was  comparatively  little  evidence  of  acidosis.  The  wide 
variations  obtained  by  this  colorimetric  method  do  not 
affect  the  general  conclusion  regarding  the  constancy  of 
the  reaction  of  the  blood  as  established  by  numerous 
determinations  of  various  workers  using  standard  phys- 
icochemical equipment.  Indeed  any  method  for  the 
detection  of  moderate  grades  of  acidosis,  depending 
upon  the  changes  in  the  hydrogen  ion  concentration  of 
the  blood,  could  only  be  considered  in  the  light  of  our 
present  knowledge,  as  being  based  upon  a  faulty  prin- 
ciple, since  it  is  established  that  no  change  occurs 
except  in  advanced  stages. 

In  the  consideration  of  acidosis,  the  carbon  dioxide 
content  of  the  blood  and  alveolar  air  are  so  closely  in- 
terdependent that  for  general  purposes  they  may  be 
considered  together.  They  depend  of  course  upon  a 
common  factor,  i.  e.,  the  content  of  the  blood  in  car- 
bonates and  ordinarily  the  agreement  between  them 
is  very  close.  This  has  been  demonstrated  in  a  recent 
study  by  Walker  and  Frothingham.15  In  a  series  of 
over  100  observations  on  thirty  different  types  of  dis- 
ease, significant  variation  in  these  factors  occurred  in 
very  few  instances.  The  analysis  of  the  carbon  dioxide 
content  of  the  blood  is  now  feasible  as  a  laboratory  pro- 
cedure by  the  principle  recently  devised  by  Van  Slyke, 


METHODS  OF  DIAGNOSING  ACIDOSIS       21 

Cullen  .and  Stillman.16  The  determination  of  the  carbon 
dioxide  content  of  the  alveolar  air  is  even  simpler  by  the 
ingenious  method  recently  devised  by  Marriott;  17  if 
this  method  is  employed,  one  should  be  in  a  position  to 
standardize  the  results  occasionally  with  more  elabo- 
rate equipment.  Unfortunately  the  carbon  dioxide  con- 
tent is  lowered  by  conditions  other  than  acidosis  or  at 
least  in  which  the  existence  of  acidosis  has  yet  to  be 
established.  The  most  significant  paper  bearing  on  this 
point  is  that  of  Porges,  Leimdbrfer  and  Markovici.18 
In  a  series  of  advanced  cardiac  cases,  many  of  which 
were  decompensated,  but  without  prominent  signs  of 
nephritis,  they  found  a  pronounced  lowering  of  the  car- 
bon dioxide  tension  of  the  alveolar  air.  Similar  changes 
are  observed  in  normal  people  accustomed  to  living  at 
high  altitudes  but  other  evidences  of  acidosis  have  not 
been  demonstrated  in  these  individuals.19 

There  are  at  least  two  general  groups  of  factors  other 
than  acidosis  which  lower  the  carbon  dioxide  tension  in 
the  alveolar  air,  namely  (1)  increased  pulmonary  venti- 
lation as  illustrated  by  the  effect  of  high  altitudes  and 
(2)  any  change  in  the  lungs  or  in  the  circulation  which 
would  interfere  with  the  exchange  of  gases  between  the 
alveolar  air  and  the  blood.  Such  changes  probably  ac- 
count for  the  low  values  found  in  some  of  the  cardiac 
cases.  A  moderate  fall  in  the  carbon  dioxide  content 
of  the  blood  or  alveolar  air  is  not  adequate  proof  of  the 
existence  of  acidosis  in  unknown  conditions  without  the 
support  of  confirmatory  evidence. 

Such  confirmation  may  often  be  obtained  from  the 
examination  of  the  urine.  One  may  search  either  for 
the  presence  of  abnormal  acids  or  for  evidence  of  exces- 
sive excretion  either  of  free  acids  or  their  neutral  salts. 


22  THE  PRINCIPLES  OF  ACIDOSIS 

The  neutralization  of  acid  by  fixed  bases  leads  to  the 
excretion  of  an  excess  of  sodium,  potassium,  calcium 
and  magnesium  in  the  urine.  Cammidge  20  has  studied 
the  excretion  of  these  elements  and  the  results  are  of 
interest  and  importance.  When  considered  as  a  clinical 
test,  two  serious  objections  present  themselves.  The 
determination  of  even  the  calcium  and  magnesium  is  too 
complicated  a  procedure  for  routine  work.  Moreover, 
the  excretion  of  calcium  and  magnesium  may  decrease 
rapidly  even  in  advanced  grades  of  acidosis  on  account 
of  a  depletion  in  the  supply  of  available  amounts  of 
these  salts  in  the  body.  Consequently  the  determina- 
tions must  be  made  not  on  any  single  day  but  through- 
out the  entire  period  of  acidosis  if  their  significance  is 
to  be  properly  interpreted. 

The  one  most  serious  objection  to  searching  for  the 
appearance  of  acids  not  encountered  in  normal  urine  is 
that  such  a  procedure  cannot  constitute  a  general 
method  for  determining  the  presence  or  absence  of  aci- 
dosis in  an  unknown  condition.  Since  these  new  acids 
might  vary  widely  in  different  acidoses,  negative  results 
might  merely  indicate  failure  to  recognize  some  un- 
known acid.  Theoretically  it  is  not  even  necessary  that 
excessive  amounts  of  acid  should  appear  in  the  urine  in 
the  development  of  an  acidosis,  but  on  the  contrary 
even  the  normal  amount  of  acid  may  be  diminished  in 
case  of  impairment  in  the  ability  of  the  kidney  to  ex- 
crete acid.  Even  when  the  kidney  is  normal  the  de- 
termination of  the  total  daily  acidity  is  not  helpful 
either  as  a  means  of  detection  or  as  a  method  of  measure- 
ment of  the  degree  of  acidosis. 

The  choice  of  methods  might  seem  to  fall  upon  the 
determination  of  ammonia;    for,  while  it  is  markedly 


METHODS  OF  DIAGNOSING  ACIDOSIS       23 

increased  in  certain  primary  disturbances  of  protein 
metabolism  in  which  no  acidosis  is  present,  yet  a  normal 
ammonia  output  might  seem  to  exclude  acidosis.  A 
priori,  however,  this  does  not  follow.  None  of  these 
procedures  are  entirely  adequate  for  a  thorough  study 
of  unknown  conditions.  It  is  now  established  that 
fatal  acidosis  may  occur  with  a  normal  or  subnormal 
output  of  ammonia  and  under  conditions  in  which  there 
is  no  disturbance  of  carbohydrate  metabolism.  These 
rather  radical  modifications  in  our  conceptions  of  acido- 
sis have  come  about  through  the  study  of  various  types 
of  kidney  disease.  In  order  to  form  a  comprehensive 
view  of  these  fundamental  changes  it  is  necessary  to 
review  in  detail  the  methods  by  which  the  occurrence  of 
acidosis  in  the  nephropathies  has  been  demonstrated. 


IV 


BEHAVIOR  OF  THE  BODY  IN  HEALTH  AND   IN 
ACIDOSIS  TOWARDS  SODIUM  BICARBONATE 

The  constancy  of  the  physicochemical  reaction  of  the 
blood  even  in  the  outspoken  stages  of  acidosis  does  not 
in  any  sense  imply  that  there  is  but  little  change  from 
the  normal  in  the  body  metabolism.  In  fact  it  is  only 
by  extensive  compensatory  changes  that  the  reaction 
is  maintained  at  a  constant  value.  The  underlying 
problem  in  the  diagnosis  of  acidosis  consists  in  the  de- 
tection of  the  changes  by  which  this  compensation  is 
effected.  Inasmuch  as  the  ultimate  object  of  this  com- 
pensation is  the  conservation  of  the  supply  of  fixed 
bases,  it  would  be  desirable  to  study  the  content  of  the 
tissues  in  these  bases  and  their  rate  of  excretion.  For 
the  reasons  that  have  already  been  pointed  out  the 
direct  analysis  of  the  urine  for  calcium,  magnesium, 
sodium  and  potassium  is  a  complicated  procedure. 
Moreover,  in  addition  to  determining  the  composition 
of  the  urine,  it  is  equally  desirable  to  learn  whether  the 
blood  and  other  tissues  of  the  body  have  become  de- 
pleted in  these  bases.  To  arrive  at  this  information,  it 
occurred  to  me  to  take  advantage  of  the  following  in- 
direct procedure.21  Under  normal  conditions,  the  inges- 
tion of  a  small  amount  of  sodium  bicarbonate  (5  grains) 
is  promptly  followed  by  the  excretion  of  at  least  part 
of  this  amount  in  the  urine,  the  reaction  of  the  urine  to 
litmus  paper  changing  from  acid  to  alkaline.  In  a 
physiological  sense,  the  tissues  are  saturated  with  alkali 

24 


TOLERANCE  TO  BICARBONATE      25 

and  the  excess  is  promptly  eliminated.  However,  if 
some  depletion  has  occurred,  the  bicarbonate  upon 
introduction  is  stored  in  the  tissues  to  make  up  this 
deficit  and  the  urine  remains  acid  in  its  reaction.  One 
of  the  essential  features  in  the  development  of  this 
phenomenon  for  detecting  acidosis  consists  in  determin- 
ing the  delicacy  of  such  a  test.  Its  sensitiveness  would 
depend  primarily  upon  two  factors,  namely,  (1)  whether 
an  early  depletion  of  fixed  bases,  even  though  very 
slight,  takes  place  in  acidosis  and  (2)  whether  the  tis- 
sues when  slightly  depleted  in  bases  will  take  up  and 
store  alkali  before  the  kidney  can  excrete  it.  In  order 
to  answer  these  questions,  the  behavior  of  the  body  to 
bicarbonate  was  studied  in  some  acidoses  occurring 
spontaneously  and  in  others  of  slight  degree  which 
were  produced  experimentally. 

The  use  of  bicarbonate  as  a  diagnostic  test  for  acidosis 
was  first  investigated  in  the  study  of  a  series  of  cases  of 
Asiatic  cholera;  in  this  disease,  renal  complications  oc- 
cur with  great  intensity,  developing  in  many  instances 
into  uraemia  with  a  rather  typical  air  hunger.  Cases  in 
the  stage  of  reaction  in  which  nephritis  had  developed 
showed  an  outspoken  tolerance  to  sodium  bicarbonate, 
the  urine  very  frequently  remaining  sharply  acid  after 
the  intravenous  injection  of  30,  60  and  even  90  grams 
of  sodium  bicarbonate;  in  normal  individuals  the  in- 
jection of  3  to  5  grams  rendered  the  urine  alkaline.21 

It  does  not  necessarily  follow  that  this  failure  to  ex- 
crete the  bicarbonate  was  due  either  to  the  nephritis  of 
Asiatic  cholera  or  that  it  was  even  the  result  of  an  acido- 
sis. At  the  time  this  work  was  carried  out,  it  seemed 
extremely  probably  that  the  tolerance  was  related  di- 
rectly to  the  renal  lesions,  rather  than  to  the  enteritis, 


26  THE  PRINCIPLES  OF  ACIDOSIS 

and  that  it  constituted  an  acidosis.  In  order  to  decide 
these  points  the  first  step  obviously  consisted  in  deter- 
mining whether  this  same  tolerance  occurs  in  nephritis 
from  other  causes.  In  Manila  where  the  cases  of  cholera 
were  studied,  uncomplicated  cases  of  nephritis  with 
typical  uraemia  are  not  very  common.  Somewhat 
later,  however,  some  ordinary  nephritics  were  studied 
in  Baltimore.22  It  was  found  in  several  instances  that 
the  bicarbonate  was  readily  excreted  even  in  outspoken 
cases  of  the  chronic  parenchymatous  type.  However, 
in  the  chronic  interstitial  type,  in  the  arteriosclerotic 
group  and  in  acute  cases,  a  high  degree  of  tolerance  was 
present  which  was  often  equal  to  or  greater  than  that 
found  in  cholera  nephritics.  Moreover,  some  of  these 
cases  were  free  from  any  bacterial  infection.  This 
proves  that  the  increased  tolerance  occurs  independently 
of  the  infection  with  the  cholera  vibrio  and  also  inde- 
pendently of  other  infections  as  well.  This  behavior  to 
bicarbonate  in  renal  disease  has  been  demonstrated 
independently  of  my  own  work  by  Palmer  and  Hender- 
son.23 Obviously,  however,  this  finding  does  not  con- 
stitute proof  of  acidosis  in  nephritis.  From  this  evidence 
alone,  it  is  altogether  impossible  to  decide  whether 
retention  of  bicarbonate  is  due,  on  the  one  hand,  to  an 
inability  of  the  diseased  kidney  to  excrete  alkali  even 
after  massive  injections  have  been  used  with  a  resulting 
accumulation  of  an  enormous  excess  of  carbonate  in  the 
body,  or  on  the  other  hand,  whether  the  diseased  kidney 
can  excrete  carbonates  in  an  approximately  normal 
manner  and  the  tissues  are  storing  the  injected  carbon- 
ates to  replace  a  deficit  existing  in  the  body. 

There  is  considerable  evidence  that  this  tolerance  rep- 
resents essentially  a  deficit  in  bases,  i.  e.,  that  it  con- 


TOLERANCE  TO  BICARBONATE  27 

stitutes  an  acidosis.  One  striking  feature  is  the  effect 
of  repetitions  of  the  injections  in  nephritic  patients. 
Many  of  these  cases  require  relatively  enormous 
amounts  of  bicarbonate,  100  grams  or  more  at  the  first 
test,  to  render  the  urine  alkaline.  It  is  characteristic 
of  these  cases  that  after  the  injections  are  discontinued 
and  the  urine  has  again  become  acid,  a  small  dose  of 
bicarbonate  (5  grams)  is  often  sufficient  to  render  the 
urine  alkaline.  It  is  very  tempting,  indeed,  to  look  upon 
this  result  as  proof  of  acidosis.  Indeed,  this  finding  has 
even  been  interpreted  in  the  literature  23  as  crucial  evi- 
dence in  the  distinction  between  acidosis  and  renal 
retention,  a  conclusion  which  is  not  fully  justified. 
Experimental  demonstration,  however,  of  the  exact 
signficance  of  this  finding  constitutes  a  rather  tedious 
problem ;  from  one  standpoint  the  prompt  effect  of  this 
small  second  injection  is  exactly  the  result  that  one 
would  expect  if  the  threshold  of  the  kidney  for  the  ex- 
cretion of  bicarbonate  had  been  raised,  the  impairment 
of  renal  function  requiring  that  excessive  amounts  be 
present  in  the  blood  before  any  bicarbonate  could  pass 
the  kidney.  After  a  sufficiently  massive  dose  of  bicar- 
bonate had  been  injected,  additional  small  doses  would 
be  excreted  by  the  kidney,  since  the  body  presumably 
could  not  rid  itself  promptly  of  this  large  injection  of 
bicarbonate.  Indeed  it  is  rather  striking  that  the  be- 
havior of  nephritic  patients  to  bicarbonate  is  just  the 
reverse  of  the  results  in  classical  diabetic  acidosis. 
In  the  treatment  of  diabetic  coma  one  of  the  distress- 
ing features  is  the  promptness  with  which  acidosis 
returns.  Thus  it  frequently  requires  rather  heroic  in- 
jections of  alkali  to  overcome  the  acidosis  and  render 
the  urine  temporarily  alkaline.    In  a  few  hours  with  the 


28  THE  PRINCIPLES  OF  ACIDOSIS 

return  of  the  acid  reaction  of  the  urine,  it  is  often  found 
that  instead  of  a  small  dose  of  alkali,  massive  injections 
are  again  required  to  bring  back  the  alkaline  reaction. 

The  differentiation  between  a  deficit  of  bases  and 
renal  retention  of  an  excess  of  bicarbonate  is  evidently 
of  fundamental  importance.  Although  the  natural  in- 
terpretation is  that  of  acidosis  (bicarbonate  deficit),  yet 
it  is  not  altogether  a  simple  matter  to  support  this  hy- 
pothesis with  exact  proof.  Successive  repetitions  at 
short  intervals  of  the  determination  of  the  tolerance  to 
bicarbonate  in  the  same  individual  are  clearly  inade- 
quate to  solve  this  problem  since,  theoretically,  one 
would  obtain  precisely  the  same  result  either  in  the  case 
of  renal  retention  or  in  a  slowly  developing  acidosis. 
Consequently,  it  becomes  necessary  to  devise  other 
methods. 

In  the  solution  of  this  problem,  the  following  evidence 
was  collected: 24 

1.  Determinations  showing  that  the  injected  bicar- 
bonate is  not  excreted  by  way  of  the  intestine. 

2.  Demonstration  that  a  deficit  of  fixed  bases  exists 
in  the  body  and  that  the  bicarbonate  does  not 
accumulate  in  excessive  amounts  in  the  blood. 

3.  Determinations  showing  a  marked  lowering  of 
the  carbon  dioxide  content  of  the  blood  in 
uraemia. 

It  is  not  a  difficult  matter  to  prove  that  the  injected 
bicarbonate  is  not  excreted  as  such  from  the  body.  Ex- 
amination of  the  urine  excludes  the  possibility  of  excre- 
tion as  such  by  the  kidney  as  long  as  the  urine  remains 
sharply  acid.  In  some  fatal  cases  of  uraemia,  which  had 
received  massive  injections,  examination  of  the  stools 
during  life  and  of  the  intestinal  contents  at  autopsy 


TOLERANCE  TO  BICARBONATE      29 

showed  no  fixed  bases.  The  stools  and  intestinal  con- 
tents were  either  acid  in  reaction,  or  where  an  alkaline 
reaction  was  obtained,  the  alkalinity  was  due  to  am- 
monium salts  and  not  to  fixed  bases.  In  order  to  distin- 
guish between  ammonia  and  the  fixed  bases,  those  stools 
which  were  alkaline  were  diluted  with  water  and  boiled 
over  a  free  flame,  the  volume  being  maintained  by  the 
addition  of  water.  Ammonia  was  driven  off  in  the  steam 
and  the  reaction  of  the  liquid  became  neutral  or  acid. 

After  determining  that  the  bicarbonate  was  not  elim- 
inated from  the  body,  it  was  necessary  to  establish 
whether  it  was  retained  as  such  in  the  tissues  to  replace 
a  preexisting  deficit  with  elimination  in  the  urine  as 
soon  as  this  deficit  was  replaced  and  also  to  determine 
whether  any  accumulation  in  excess  of  the  normal  oc- 
curred. The  most  direct  method  for  investigating  these 
points  would  consist  in  the  estimation  of  the  titratable 
alkalinity  of  the  blood.  This  was  accomplished  indi- 
rectly by  the  determination  of  the  carbonates  as  carbon 
dioxide  and  directly  by  the  use  of  indicators.  The 
usual  titration  methods  of  whole  serum  with  indicators 
are  not  sufficiently  definite  to  admit  of  rigid  conclusions. 
A  simple  qualitative  method  was  devised  by  which  it 
was  possible  to  detect  a  diminution  in  titratable  alkalin- 
ity of  the  blood  and  to  determine  the  fate  of  the  injected 
bicarbonate.25  The  basis  of  this  method  is  that  normal 
blood  serum  reacts  as  an  acid  to  phenolphthalein  but 
heated  serum  reacts  alkaline.  In  order  to  render  the 
test  more  sensitive,  the  interfering  proteins  were  re- 
moved by  alcohol.  The  titratable  value  of  the  proteins 
is  lost  in  this  procedure  but  the  object  of  this  test  is 
to  detect  qualitative  changes  with  absolute  certainty 
rather  than  to  attempt  the  accurate  measurement  of 


30  THE  PRINCIPLES  OF  ACIDOSIS 

comparatively  small  quantitative  changes  under  un- 
favorable conditions.  A  simple  way  of  carrying  out 
this  test  is  as  follows:  one  c.c.  of  serum  is  shaken 
thoroughly  for  a  moment  with  25  c.c.  of  absolute  alcohol 
and  the  alcohol  filtered  off.  The  filtrate  with  a  few 
drops  of  phenolpthalein  is  evaporated  to  dryness. 
With  normal  human  serum,  the  residue  is  always  red. 
In  mild  grades  of  acidosis,  the  residue  is  either  colorless 
or,  on  close  observation,  one  may  detect  just  a  trace  of 
pink  color,  but  an  intense  red  color  appears  on  adding 
a  drop  of  water.  In  more  marked  grades  of  acidosis, 
the  residue  is  colorless  and  remains  colorless  on  adding 
water.  In  extreme  cases,  the  diluted  serum  without 
removal  of  proteins,  when  boiled,  remains  colorless 
upon  the  addition  of  phenolphthalein.  The  value  of 
this  method  was  tested  both  by  experimentation  in 
vitro  and  in  vivo.  Small  amounts  of  acid  were  added 
to  blood  serum.  This  addition  of  acid  could  be  detected 
much  more  readily  by  testing  the  reaction  to  phenol- 
phthalein than  by  titrating  against  standard  acid  using 
dimethylamidoazobenzene  (Topfer's  reagent)  as  indi- 
cator. Experimental  acidosis  in  animals  and  spon- 
taneous acidosis  arising  in  man  could  also  be  detected 
very  readily.25  All  nephritics  which  show  an  increase 
in  tolerance  of  20  to  30  grams  or  more  of  sodium  bicar- 
bonate also  show  changes  in  blood  when  tested  in  this 
manner  with  phenolphthalein.  The  results  of  the  exam- 
ination of  the  blood  in  a  typical  case  of  uraemia  and  the 
effect  of  the  injection  of  bicarbonate  are  presented  in 
some  detail,  since  two  important  conclusions  are  drawn 
from  these  findings.  The  data  prove  in  the  first  place 
that  the  diseased  kidney  can  excrete  bicarbonate  very 
readily,  and  secondly,  that  a  method  is  afforded  for 


TOLERANCE  TO  BICARBONATE 


31 


demonstrating  the  existence  of  definite  acidosis  rather 
early  in  the  course  of  nephritis.  These  conclusions  are 
based  upon  a  preliminary  study  of  fourteen  cases  22 
followed  by  a  more  complete  study  of  seventeen  addi- 
tional cases.24  The  following  table  illustrates  typical 
cases : 

TITRATABLE  ALKALINITY  OF  THE  BLOOD  IN  URAEMIA  AND 

THE  EFFECT  OF  THE  INJECTION  OF  SODIUM 

BICARBONATE 


Behavior  of  serum  towards 

phenolphthalein  after  re- 

Sodium 

Interval 

moval  of  protein 

1-10  di- 
lution 

Carbon 
dioxide 
in  blood 

Reaction  of 

Case 

bicar- 
bonate 

injec- 
tions 

Alco- 
holic so- 

Residue 
after 

Aqueous 
solution 

of  whole 
serum 

(volume 
per 

urine  to 
litmus 

lution  of 

evapo- 

of 

in  water 

cent) 

residue 

ration 

residue 

Before  in- 

No color 

No  color 

No  color 

No  color 

20 

Acid 

jection 

1 

60  gm. 

12  hrs. 

No  color 

No  color 

Pink 

Pink 

.... 

Acid 

60  gm. 

12  hrs. 

No  color 

Pink 

Red 

Red 

Acid 

30  gm. 

8  hrs. 

Red 

Red 

Red 

Red 

44 

Neutral 

Before  in- 

No color 

No  color 

No  color 

No  color 

22 

Acid 

jection 

2 

30  gm. 

20  hrs. 

No  color 

No  color 

Pink 

Red 

.... 

Acid 

30  gm. 

20  hrs. 

Red 

No  color 

Red 

Red 

Acid 

20  gm. 

5  hrs. 

Red 

Red 

Red 

Red 

50 

Slightly 
alkaline 

Normal 

5  gm. 

3  hrs. 

Red 

Red 

Red 

Red 

40  to  50 

Acid 
Alkaline 

In  this  table  the  colorless  reaction  to  phenolphthalein 
shows  that  originally  the  blood  was  seriously  depleted 
in  fixed  bases.  With  the  successive  injections  of  bicar- 
bonate, the  reaction  to  phenolphthalein  passes  through 
the  various  stages  showing  that  the  carbonate  content 
of  the  blood  is  gradually  increasing.  During  these  in- 
jections the  urine  remains  acid  in  reaction,  until  the 


32  THE  PRINCIPLES  OF  ACIDOSIS 

point  is  reached  at  which  the  blood  serum  reacts  nor- 
mally; then  a  further  injection  of  alkali  causes  the  urine 
to  become  alkaline. 

Confirmation  of  these  conclusions  was  obtained  by 
determining  the  carbon  dioxide  content  of  venous 
blood.  For  making  these  determinations,  a  modifica- 
tion was  devised  of  Warburg's  method  for  estimating 
small  amounts  of  carbon  dioxide.24  This  modification 
was  developed,  not  for  the  purpose  of  providing  a  routine 
method,  but  rather  to  determine  accurately  whether  a 
definite  and  significant  drop  in  carbon  dioxide  occurs 
in  uraemia.  This  is  of  considerable  importance  since 
an  extreme  fall  in  the  carbon  dioxide  content  of  the 
venus  blood  is  virtually  pathogonomonic  of  acidosis. 
The  results  showed  a  pronounced  lowering.  In  four 
typical  cases  of  uraemia  the  values  ranged  from  10  to 
24  per  cent,  calculated  as  volumes  per  cent,  instead  of  a 
normal  of  40  to  50  per  cent. 

This  evidence,  obtained  then  from  the  examination 
of  the  stools  and  urine  and  the  titratable  alkalinity  and 
carbon  dioxide  content  of  the  blood,  gives  absolute 
proof  that  the  tolerance  to  fixed  bases  in  nephritis  is 
due  essentially  to  a  deficit  of  the  body  in  bases  and  not 
to  an  inability  of  the  kidney  to  excrete  bases  nor  to 
vicarious  excretion  of  bicarbonate  by  the  intestine. 
This  evidence  is  supported  by  a  variety  of  circumstances 
but  it  constitutes  the  only  exact  proof  which  we  have 
that  this  increase  in  tolerance  in  early  cases  of  nephritis 
is  due,  primarily,  to  a  deficit  in  fixed  bases  and  not  to  a 
retention  of  the  injected  carbonate  in  excess  of  the 
normal  requirements  of  the  body.  At  the  same  time 
it  is  possible  that  a  minimal  amount  of  bicarbonate  may 
be  retained  on  account  of  renal  lesions,  just  as  the  ex- 


TOLERANCE  TO  BICARBONATE  33 

cretion  of  sugars  and  dyes  is  partially  suppressed  in 
certain  types  of  nephritis,  even  in  comparatively  mild 
cases.  This  introduces  the  possibility  that  a  very 
minor  and,  from  the  standpoint  of  acidosis,  an  insignifi- 
cant proportion  of  the  increase  in  tolerance  is  due  to 
renal  retention.*  Consequently,  it  is  not  of  vital  im- 
portance whether  one  refers  to  this  phenomenon  as  "  a 
deficit  in  bicarbonate  "  as  strongly  recommended  by 
Palmer  and  Henderson,23  or  whether  it  is  called  "  tol- 
erance to  bicarbonate  "  in  the  sense  that  I  have  de- 
scribed in  greater  detail  in  a  previous  paper.25  The 
expression  '  tolerance  to  bicarbonate '  has  the  ad- 
vantage of  uniformity  with  the  nomenclature  of  other 
tests  in  clinical  medicine  which  are  analogous  to  this 
one;  being  a  general  term,  it  is  rather  more  accurate 
since  it  includes  any  possible  minor  factors  as  well  as 
the  major  factor,  "  deficit  in  bicarbonate."  All  in  all, 
the  more  general  term  "  tolerance  to  bicarbonate  "  is 
preferable  since  it  is  obviously  impracticable  to  describe 
the  exact  mechanism  of  a  phenomenon  in  the  few  words 
of  a  title. 

*  These  data  establishing  this  conclusion  are  not  taken  into  consideration 
by  Rowntree  in  his  very  recent  criticism  that  the  alkali  tolerance  test  in  renal 
insufficiency  is  useless  and  misleading.14  Rowntree  also  considers  that  the 
carbonates  are  comparable  to  other  substances  used  in  testing  renal  function, 
but  it  must  be  pointed  out  again  that  a  fundamental  difference  exists.  As  a 
rule,  only  partial  and  very  incomplete  suppression  of  substances  results  from 
renal  insufficiency  even  after  the  administration  sometimes  of  very  minute 
amounts;  in  contrast  to  this  behavior,  when  substances  are  stored  to  make 
up  a  deficit  in  the  tissues  relatively  enormous  amounts  can  be  administered 
often  without  even  a  trace  appearing  in  the  urine.  By  way  of  illustration,24 
in  seven  cases  of  uraemia  the  administration  of  30  to  160  grams  of  bicarbonate 
was  not  followed  in  any  instance  by  an  alkaline  urine.  In  these  same  cases, 
0.6  to  1.2  milligrams  of  phenolsulphonepthalein  and  5  to  10  grams  of  lactose 
was  not  completely  retained  in  any  instance. 


RELATIVE  VALUE  OF  THE  VARIOUS  TESTS 
FOR  ACIDOSIS 

In  forming  an  opinion  of  the  relative  value  of  the  labo- 
ratory methods  for  detecting  acidosis,  it  is  well  to  con- 
sider the  order  in  which  the  various  tests  would  appear 
in  the  gradual  development  from  normal  conditions  to  a 
state  of  advanced  acidosis.  While  no  one  has  worked 
out  the  exact  sequence,  still  their  relative  position  is,  in 
general,  fairly  well  known.  Minor  variations  neces- 
sarily occur  in  individual  cases  and  in  acidoses  of  various 
etiology,  yet  sufficient  data  are  available  for  the  con- 
struction of  the  following  outline,  giving  the  tests  in  the 
order  of  their  delicacy: 

1.  Appearance  of  acetone  bodies  in  the  urine  (for 
carbohydrate  acidosis  only). 

2.  Increase  in  tolerance  to  sodium  bicarbonate. 

3.  Lowering  of  the  carbon  dioxide  of  the  alveolar 
air  and  of  the  blood. 

4.  Change  in  reaction  to  phenolphthalein,  from 
alkaline  to  neutral,  of  protein  free  filtrate  from 
blood  serum. 

5.  Increase  in  output  of  ammonia  in  urine 
(usually  normal  in  nephritic  acidoses). 

6.  Increase  in  hydrogen  ion  concentration  of  the 
blood. 

The  appearance  of  acetone  bodies  is,   unfortunately, 
limited  to  diabetes  or  to  disturbances  of  the  carbohy- 

34 


RELATIVE  VALUE  OF  VARIOUS  TESTS       35 

drate  metabolism.  Moreover,  a  slight  increase  in  the 
normal  output  of  acetone  occurs  so  easily  (sometimes 
with  twelve  hours  fasting)  that  it  does  not  indicate  any 
depletion  of  the  fixed  bases.  Furthermore,  definite 
acidosis  may  develop  in  diabetes  without  the  appear- 
ance of  acetoacetic  acid  in  the  urine  and  when  the  out- 
put of  acetone  and  ammonia  is  within  normal  limits. 
There  is  one  precaution  which  should  be  observed  in 
the  consideration  of  acidoses  due  to  /3-oxybutyric  acid. 
For  example  in  typical  diabetic  acidosis  the  fixed  bases 
become  depleted.  Then,  if  the  excretion  of  /3-oxybu- 
tyric  acid  were  suddenly  stopped  by  the  administration 
of  carbohydrates,  the  acidosis,  i.  e.,  the  depletion  of  the 
alkali  reserve,  would  persist  for  some  time.  The  toler- 
ance to  bicarbonate  would  be  abnormally  high  but 
there  would  be  no  acetone  in  the  urine.  Thus,  in  the 
examination  of  urine  in  diabetes,  the  expression  "  ace- 
tone free  "  does  not  necessarily  have  the  same  signifi- 
cance as  "  sugar  free."  In  other  words  it  does  not 
always  signify  that  metabolism  is  normal  and  that  the 
patient  is  necessarily  free  from  acidosis.  Evidently, 
considerable  precaution  is  necessary  in  drawing  con- 
clusions regarding  acidosis  from  the  examination  of  the 
urine  for  acetone  in  diabetes,  since  the  presence  of  ace- 
tone does  not  establish  the  existence  of  acidosis,  and  its 
absence  by  no  means  proves  the  absence  of  acidosis. 
A  similar  relationship  pertains  between  the  acetone 
bodies  and  acidosis  in  children.  This  subject  has  been 
thoroughly  discussed  by  Howland  and  Marriott.26 

In  the  preceding  outline,  the  position  of  carbon  diox- 
ide in  the  blood  and  in  the  alveolar  air  is  extremely 
difficult  to  place,  partly  on  account  of  its  comparatively 
wide  normal  range  and  also  because  conditions  other 


36  THE  PRINCIPLES  OF  ACIDOSIS 

than  acidosis  may  produce  a  slight  lowering  of  the  car- 
bon dioxide.  Hence  as  regards  the  relative  position 
which  the  lowering  of  the  carbon  dioxide  bears  to  the 
other  tests,  it  is  necessary  to  decide  whether  one  is  to 
take  into  account  only  those  changes  which  are  char- 
acteristic of  acidosis  or  whether  one  is  to  consider  also 
those  earlier  changes  which  may  likewise  be  produced 
by  other  conditions.  Even  considering  the  earliest 
changes  that  are  definitely  demonstrable,  the  position 
of  carbon  dioxide  cannot  be  placed  higher  than  it  ap- 
pears in  the  preceding  list.  On  the  other  hand,  if  one 
considers  only  the  outspoken  changes  which  would  of 
themselves  be  absolutely  pathogonomonic  of  acidosis, 
then  its  position  would  be  much  lower  in  the  scale,  per- 
haps just  preceding  the  change  in  the  hydroxyl  ion  con- 
centration of  the  blood. 

In  developing  the  method  for  testing  the  reaction  of 
the  protein  free  filtrate  from  the  serum  with  phenol- 
phthalein,  I  did  not  attempt  to  adjust  this  to  its  greatest 
possible  delicacy,  but  rather  to  use  it  under  conditions 
in  which  a  change  from  the  normal  could  be  depended 
upon  to  indicate  acidosis.  In  its  present  form,  it  served 
to  demonstrate  that  the  increase  in  tolerance  to  bicar- 
bonate in  the  nephropathies  is  essentially  a  bicarbonate 
deficit.  Without  further  refinement  it  is  also  sufficiently 
delicate  to  detect  acidosis  of  any  clinical  significance. 
It  is  not  only  of  diagnostic  value  but  is  of  considerable 
help  in  regard  to  therapy.  Thus  it  enables  one  to  de- 
cide whether  the  administration  of  alkalies  is  advisable 
and  whether  the  amount  required  will  be  sufficiently 
large  to  necessitate  intravenous  injection.  Also,  when 
massive  doses  of  alkali  are  being  injected  it  is  only  by 
examination  of  the  blood  or  alveolar  air  that  one  can 


RELATIVE  VALUE  OF  VARIOUS  TESTS   37 

determine  when  the  injections  should  be  diminished  in 
order  to  avoid  overstepping  too  far  the  amount  re- 
quired to  change  the  reaction  of  the  urine.  The  exami- 
nation of  the  urine  gives  practically  no  warning  of  the 
approaching  change  from  an  acid  to  an  alkaline  re- 
action. 

The  study  of  the  excretion  of  ammonia  is  not  so  help- 
ful in  the  diagnosis  of  acidosis  as  was  formerly  supposed. 
The  ammonia  coefficient  may  be  high  in  primary  dis- 
turbances of  protein  metabolism  or  may  be  low  in  out- 
spoken acidoses. 

It  is  not  necessary  to  emphasize  further  the  lack  of 
clinical  value  of  determinations  of  the  changes  in  the 
hydrogen  ion  concentration  of  the  blood  for  the  early 
detection  of  acidosis. 

The  increase  in  the  tolerance  to  bicarbonate  (the  "  bi- 
carbonate deficit  ")  is  the  most  delicate  of  the  tests 
which  are  specific  for  acidosis.  By  the  use  of  this  test, 
it  was  possible  to  detect: 

1.  Very  slight  grades  of  experimental  acidosis  in 
man  resulting  from  two  to  three  days  of  car- 
bohydrate free  diet  or  from  the  ingestion  of 
about  2  to  3  grams  of  dilute  hydrochloric  acid 
over  a  period  of  four  or  five  days. 

2.  Moderate  grades  of  acidosis  in  diabetic  cases 
which  show  no  excess  of  acetone  or  ammonia 
over  the  normal. 

3.  Moderate  acidosis  in  comparatively  early  cases 
of  nephritis. 

In  cases  of  early  acidosis,  this  tolerance  to  bicarbonate 
showed  a  definite  increase  at  a  time  when  the  blood  was 
still  normal  as  regards  its  content  in  carbon  dioxide  and 


38  THE  PRINCIPLES  OF  ACIDOSIS 

its  reaction  to  phenolphthalein  and  when  the  urine  did 
not  show  any  change  in  its  ammonia  output  and  did 
not  give  any  evidence  of  the  existence  of  an  acidosis. 
Moreover,  when  the  tolerance  to  bicarbonate  is  normal, 
then  acidosis  can  be  excluded. 

The  choice  of  clinical  tests  will  of  course  be  influenced 
in  a  large  measure  by  circumstances  and  by  the  purpose 
which  one  has  in  view.  For  example  the  diagnosis  of 
early  stages  of  acidosis  in  nephritis  is  a  different  prob- 
lem from  the  regulation  of  alkaline  therapy  in  advanced 
diabetic  acidosis.  Under  conditions  in  which  an  espe- 
cially delicate  test  is  required,  the  determination  of  the 
tolerance  to  bicarbonate  is  the  most  suitable  procedure. 
In  addition  to  the  delicacy  of  this  determination  it 
combines  in  one  step  a  measure  of  the  degree  of  acidosis 
and  an  appropriate  therapy. 

On  the  other  hand,  if  it  is  only  a  question  of  distin- 
guishing between  a  well  developed  acidosis  and  some 
other  form  of  dyspnoea  or  coma,  one  may  wish  to  avoid 
the  delay  of  waiting  for  urine  specimens  which  the  tests 
for  tolerance  involve.  Under  such  circumstances  one 
may  employ  either  the  determination  of  the  carbon 
dioxide  content  of  the  alveolar  air  or  the  reaction  of  the 
blood  serum  to  phenolphthalein  after  removal  of  the 
protein.  The  abundance  of  normal  reactions  that  are 
obtained  is  sometimes  a  little  disappointing  but  this 
only  serves  to  emphasize  the  comparative  rarity  in  a 
general  clinic  of  acidosis  possessing  clinical  significance. 
For  purposes  of  special  study,  where  a  series  of  obser- 
vations at  frequent  intervals  is  desired,  the  examina- 
tion of  the  alveolar  air  is  the  most  desirable  method  in 
order  to  avoid  the  repeated  venupuncture  necessary  for 
determining   the   titratable   alkalinity   or   the   carbon 


RELATIVE  VALUE  OF  VARIOUS  TESTS       39 

dioxide  content  of  the  serum.  In  the  study  of  comas, 
specimens  of  urine  may  often  be  difficult  to  secure  and 
it  is  only  recently  that  those  tests  have  been  developed 
which  render  one  independent  of  the  examination  of 
the  urine  in  the  diagnosis  of  acidosis. 

The  depletion  of  the  body  in  carbonates  and  other 
alkali  yielding  substances  constitutes,  in  the  ultimate 
analysis,  the  primary  underlying  factor  in  the  follow- 
ing tests  for  acidosis,  namely,  the  change  in  the  carbon 
dioxide  content  (1)  of  the  blood  and  (2)  of  the  alveolar 
air,  (3)  the  concentration  of  the  blood  in  hydrogen  and 
hydroxyl  ions,  (4)  the  tolerance  to  fixed  bases  and  (5) 
the  titratable  alkalinity  of  the  blood.  In  establishing, 
for  the  first  time,  the  existence  of  acidosis  in  a  given 
disease,  it  is  obviously  desirable  to  depend  upon  not 
less  than  two  methods;  relatively  little  importance 
would  attach  itself  to  any  single  test  in  the  preceding 
list,  especially  if  only  a  moderate  degree  of  change  was 
found.  The  presence  of  acidosis  in  some  of  the  earlier 
stages  of  the  nephropathies  was  proven  by  demon- 
strating an  increase  in  tolerance  to  bicarbonate  accom- 
panied by  qualitative  changes  in  the  reaction  of  the 
protein  free  filtrate  of  the  serum.  In  uraemia  and 
preuraemic  conditions,  the  occurrence  of  acidosis  was 
confirmed  by  establishing  that  the  carbon  dioxide  con- 
tent of  the  blood  was  very  markedly  decreased.  Pea- 
body  27  has  produced  proof  of  the  occurrence  of  acidosis 
in  uraemia.  The  crucial  tests  which  were  employed  by 
Peabody  were  the  determination  of  the  hydrogen  ion 
concentration  of  the  blood  and  the  carbon  dioxide  con- 
tent of  the  alveolar  air.  The  hydrogen  ion  concentra- 
tion of  the  blood  was  slightly  but  distinctly  increased  in 
uraemic  cases  a  few  days  before  death  and  there  was  a 


40  THE  PRINCIPLES  OF  ACIDOSIS 

corresponding  lowering  of  the  carbon  dioxide  tension 
of  the  alveolar  air. 

The  subject  of  acidosis  in  cardiorenal  disease  is  dis- 
cussed in  a  report  by  Lewis,  Ryffel,  Wolf,  Cotton  and 
Barcroft.28  These  authors  depended  principally  upon 
the  determination  of  the  carbon  dioxide  of  the  alveolar 
air.  Notwithstanding  the  extensive  series  of  observa- 
tions which  were  conducted,  the  evidence  is  somewhat 
contradictory  and  has  not  proven  to  be  convincing  as 
regards  the  occurrence  of  acidosis.  In  a  single  instance 
they  report  a  pressure  of  24  mm.,  in  a  case  which  they 
do  not  consider  to  be  acidosis  as  compared  with  a 
normal  range  of  36  to  42  mm.  Moreover,  they  found 
in  nine  cardiorenal  cases,  in  which  they  consider  that 
acidosis  was  present,  the  tension  of  carbon  dioxide  in 
the  alveolar  air  did  not  fall  below  25  mm.,  except  in  one 
instance;  it  was  frequently  over  30  mm.  and  occa- 
sionally as  high  as  40  mm.  These  discrepancies  are  not 
easily  explained  and  they  leave  some  doubt  as  to  the 
conclusions  which  should  be  drawn  in  these  cases. 

Straub  and  Schlayer  29  found  a  definite  lowering  of 
the  carbon  dioxide  of  the  alveolar  air  in  nephritis  but 
they  do  not  draw  any  final  conclusions  from  their  data. 
Porges  and  Leimdorfer  30  observed  that  the  tension  of 
the  carbon  dioxide  in  the  alveolar  air  is  in  general  pro- 
portional to  the  symptoms  of  uraemia.  However,  as 
already  mentioned,  these  authors  together  with  Marko- 
vici  found  a  similar  lowering  in  decompensated  cardiac 
cases,  a  condition  in  which  the  existence  of  acidosis  has 
not  yet  been  established.  In  a  later  paper,  Straub  3l 
conforms  with  the  general  view  that  the  lowering  of  the 
carbon  dioxide  tension  in  uraemia  represents  a  form  of 
acidosis. 


RELATIVE  VALUE  OF  VARIOUS  TESTS       41 

In  some  early  work  on  the  titration  values  of  the 
blood  von  Jaksch  32  found  some  low  values  in  a  variety 
of  conditions,  more  especially  in  severe  fevers  (typhoid, 
pneumonia  and  sepsis),  in  anaemia,  in  cachexias,  in 
diseases  of  the  liver  and  in  leukaemia.  Low  values 
occurred  almost  constantly  in  uraemia  though  equally 
low  results  were  found  in  a  number  of  other  conditions 
in  which  subsequent  investigations  have  not  demon- 
strated an  acidosis  comparable  even  to  that  which  may 
occur  in  mildly  uraemic  patients.  The  titration  method 
used  by  von  Jaksch  does  not  merit  confidence  and  his 
results  have  not  been  interpreted  as  establishing  the 
existence  of  acidosis  in  uraemia. 


VI 

DEFINITION  OF  ACIDOSIS 

The  term  acidosis  has  been  used  freely  in  the  litera- 
ture with  a  considerable  variety  of  meanings  and  often 
without  any  well-defined  significance;  the  variety  of 
interpretations  has  been  so  great  that,  until  recent 
years,  the  idea  of  acidosis  has  been  regarded  only  as  a 
theory.  It  is  now  generally  accepted  that  acidosis  is 
essentially  an  impoverishment  of  the  body  in  alkalies. 
This  idea  was  clearly  stated  by  Naunyn  33  in  1906  under 
the  term  hypalkalitat  and  by  Emerson  84  using  the  ex- 
pression alkali  starvation.  This  interpretation  has  re- 
ceived ample  support  from  the  investigations  of  the 
physicochemical  reaction  of  the  blood,  the  carbon  diox- 
ide content  of  the  blood  and  alveolar  air,  the  titratable 
alkalinity  of  the  blood  and  the  tolerance  of  the  body  to 
sodium  bicarbonate.  In  its  simplest  terms,  then,  acido- 
sis is  an  impoverishment  of  the  blood  and  other  tis- 
sues in  fixed  bases  or  in  substances  which  readily  give 
rise  to  fixed  bases.  Death  takes  place  before  any  signifi- 
cant change  occurs  in  the  reaction  of  the  blood;  it  re- 
mains alkaline  both  in  its  physicochemical  reaction  and 
in  its  behavior  to  indicators.  It  will  be  seen  that  there 
are  many  ways  in  which  this  depletion  in  alkali  may  be 
brought  about.  In  diabetes,  for  example,  organic  acids 
instead  of  being  destroyed  by  oxidation  are  neutralized 
by  alkalies.  In  cholera  it  is  probable  that  a  certain 
amount  of  fixed  alkali  is  lost  by  elimination  as  such  from 
the  bowel.    This  latter  type  has  sometimes  been  called 

42 


DEFINITION  OF  ACIDOSIS  43 

a  relative  acidosis  in  contrast  to  the  absolute  acidosis  of 
diabetes.  The  meaning  of  these  terms  is  extremely  in- 
definite but  there  is  a  distinct  implication  that  in  the 
relative  acidosis  there  is  less  alkali  than  normally,  while 
in  the  absolute  there  is  an  excess  of  acid.  This  is  mis- 
leading since  in  any  acidosis  there  is  simply  a  diminu- 
tion in  the  supply  of  alkali.  Accordingly  it  is  difficult  to 
ascribe  any  useful  place  to  the  terms  relative  and  abso- 
lute as  applied  to  acidosis.  Indeed,  the  terms  acidosis 
and  acid-intoxication  themselves  are  misnomers.  Their 
use  came  about  very  naturally  in  the  original  experi- 
ments where  mineral  acid  was  fed  to  animals  through 
a  stomach  tube,  and  subsequently,  the  same  terms  were 
carried  over  into  human  pathology.  Certainly,  a  more 
fortunate  expression  would  have  been  some  word  signi- 
fying hypo-alkalinity.  A  particularly  misleading  term 
which  sometimes  appears  is  the  use  of  the  word  acidae- 
mia.  This  arises  in  part  from  a  complete  indifference 
in  distinguishing  between  acids  and  their  neutral  salts. 
As  a  result,  sodium  oxybutyrate  or  sodium  chloride  are 
spoken  of  as  acids  in  the  blood. 

There  is  an  expression  compensated  acidosis  which  can 
easily  give  rise  to  confusion.  Strictly  speaking,  all  nor- 
mal individuals  are  in  a  state  of  compensated  acidosis, 
i.  e.,  normal  metabolism  gives  rise  to  an  excess  of  acid 
radicals  which  must  be  either  neutralized  or  excreted. 
Even  in  extreme  acidosis,  the  body  still  compensates 
in  a  large  measure;  the  hydrogen  ion  concentration  of 
the  blood  rises  only  a  little  even  at  death,  whereas, 
except  for  the  compensating  processes  of  the  body,  the 
amount  of  acid  that  is  produced  would  cause  a  relatively 
enormous  rise.  From  a  biochemical  standpoint,  then, 
an  acidosis  is  always  either  completely  or  partially 


44  THE  PRINCIPLES  OF  ACIDOSIS 

compensated,  and  there  is  no  wholly  uncompensated 
condition.  On  a  clinical  basis,  one  might  divide  the 
cases  into  compensated  and  partially  compensated 
groups,  according  to  the  presence  or  absence  of  clinical 
symptoms.  Such  a  division  would  necessarily  be 
rather  indefinite.  The  situation  becomes  even  more 
difficult  if  one  attempts  to  distinguish  two  groups  by 
the  measurement  of  the  hydrogen  ion  concentration  of 
the  blood.  By  such  means  the  two  groups  of  cases 
could  be  differentiated  neither  by  their  clinical  symp- 
toms nor  by  the  ordinary  laboratory  tests  for  acidosis, 
but  the  distinction  would  have  to  be  made  by  physico- 
chemical  methods.  The  transition  from  complete  to 
partial  compensation  is  extremely  gradual  and  there  is 
no  basis  on  which  the  cases  can  be  sharply  subdivided 
into  distinct  groups.  For  the  ordinary  descriptions  of 
individual  cases  it  seems  sufficient  to  express  the  rela- 
tive severity  of  the  acidosis.  If  a  definite  basis  for  the 
comparison  of  different  cases  is  desired  the  determina- 
tion of  the  tolerance  to  bicarbonate  would  be  much 
more  serviceable  than  the  measurement  of  the  hydro- 
gen ion  concentration  of  the  blood. 

It  does  appear  especially  desirable  to  limit  the  term 
acidosis  to  those  conditions  in  which  systemic  change 
occurs  so  that  the  body  as  a  whole  shows  some  systemic 
abnormality.  There  is  a  little  tendency  of  late  to  con- 
sider, as  an  acidosis,  certain  sharply  localized  accumula- 
tions of  acid.  Thus  instances  may  arise  of  a  slight  and 
well  localized  production  of  acid  in  a  bacterial  focus, 
or  as  in  Fischer's  35  tests  of  the  kidney  tissue  with  indi- 
cators for  acids.  But  the  amount  of  acid,  though  it  can 
readily  be  detected  by  indicators,  is  either  so  small  in 
amount  or  so  sharply  localized  that  it  produces  no 


DEFINITION  OF  ACIDOSIS  45 

measurable  effect  on  the  body  tissues  as  a  whole  or  the 
fluids  in  general  circulation.  Such  a  condition  is  evi- 
dently very  different  from  a  partial  depletion  of  the 
reserve  supply  of  fixed  bases  and  it  would  be  confusing 
to  include  the  two  under  one  name.  At  the  same  time, 
it  is  obvious  that  a  high  grade  bacterial  infection,  es- 
pecially if  it  is  not  localized,  might  produce  sufficient 
acid  to  lead  directly  or  indirectly  to  a  measurable  de- 
pletion of  alkalies.  The  distinction  between  a  local  and 
general  effect  might  appear  to  be  a  difficult  one.  For- 
tunately, however,  there  are  adequate  methods  which 
are  amply  delicate  for  the  detection  of  any  change  in  the 
reserve  supply  of  base.  However  at  the  commence- 
ment of  a  general  depletion,  the  division  between  nor- 
mal and  pathologic  conditions  is  entirely  quantitative 
and  necessarily  somewhat  arbitrary.  In  the  selection 
of  the  normal  standards  there  is  naturally  some  oppor- 
tunity for  a  variation  of  opinion,  but  the  crucial  point 
is  the  adoption  of  suitable  tests  by  which  the  normal 
values  shall  be  determined. 

In  the  selection  of  a  standard  test  for  the  definition 
of  acidosis,  it  is  practically  necessary  to  choose  one 
which  is  of  general  application.  This,  at  once,  elimi- 
nates the  reactions  for  acetone,  acetoacetic  and  /S- 
oxy butyric  acid,  and  the  determination  of  ammonia. 
Likewise  the  measurement  of  the  hydrogen  ion  concen- 
tration of  the  blood  obviously  is  inadequate.  A  fair 
working  basis  could  be  obtained  by  the  determination 
of  the  carbon  dioxide  content  of  the  alveolar  air  or  of 
the  blood,  or  by  the  measurement  in  the  change  of  the 
titratable  alkalinity  with  phenolphthalein,  after  the 
removal  of  the  protein.  The  changes  in  the  carbon 
dioxide,  however,  do  not  constitute  an  ideal  basis.    In 


46  THE  PRINCIPLES  OF  ACIDOSIS 

the  first  place,  the  normal  variation  is  fairly  wide. 
Moreover,  in  formulating  the  definition  of  acidosis  it  is 
important  to  consider  the  body  as  a  whole  and  not  the 
blood  alone.  This  may  be  brought  out  more  clearly  by 
referring  to  other  pathologic  processes.  In  a  number 
of  instances  when  the  body  is  becoming  impoverished 
in  certain  constituents,  a  fairly  normal  composition  of 
the  blood  is  maintained  at  the  expense  of  the  other 
tissues.  For  example,  when  a  serious  diminution  occurs 
in  the  supply  of  water  or  of  carbohydrates,  the  blood  is 
replenished  from  the  other  tissues  until  their  supply  is 
seriously  depleted.  This  phenomenon  would  seem  to 
be  a  general  law,  applicable  to  a  number  of  substances 
and  apparently  it  holds  very  well  indeed  in  the  case  of 
the  fixed  bases.  Viewed  from  this  standpoint,  acidosis 
is  fundamentally  a  diminution  in  the  supply  of  fixed  bases 
in  the  blood  and  tissues  of  the  entire  body  and  the  term 
should  not  be  limited  to  the  carbonates  nor  to  changes  in 
the  blood  alone.  In  the  definition  of  acidosis  these  limi- 
tations may  be  avoided,  at  least  in  a  large  measure, 
by  the  determination  of  the  tolerance  to  bicarbonate. 
With  this  test,  definite  proof  of  acidosis  was  obtained 
while  the  tension  of  carbon  dioxide  in  the  blood  was 
still  normal.  The  tolerance  tests  possess  the  further 
advantage  that  the  normal  values  are  relatively  con- 
stant and  the  available  evidence  indicates  that  the 
tolerance  to  bicarbonate  is  increased  only  in  acidosis. 

The  interpretation  of  the  values  obtained  in  the  bi- 
carbonate determination  is  very  simple  since  the  normal 
tolerance  is  constant  and  low  as  compared  with  the 
values  obtained  in  stages  of  acidosis  that  are  of  any 
clinical  significance.  Five  grams  of  sodium  bicarbonate 
by  mouth  is  practically  the  upper  limit  of  normal  toler- 


DEFINITION  OF  ACIDOSIS  47 

ance,  this  quantity  being  almost  invariably  sufficient,  in 
a  normal  individual,  to  change  the  reaction  of  the  urine 
from  acid  to  alkaline.  A  tolerance  of  ten  grams  could 
logically  be  considered  as  an  acidosis,  but  such  a  slight 
increase  could  not  have  any  clinical  significance  since 
the  tolerance  may  be  several  times  as  great  as  this  with- 
out the  appearance  of  clinical  symptoms. 

Acidosis,  therefore,  may  be  very  simply  and  correctly 
defined  as  a  diminution  in  the  reserve  supply  of  fixed 
bases  in  the  blood  and  other  tissues  of  the  body,  the 
physiochemical  reaction  of  the  blood  remaining  un- 
changed except  in  very  extreme  conditions.  The  defi- 
nition should  not  be  limited  to  the  carbonates  alone  but 
should  include  the  other  fixed  bases  of  the  body;  like- 
wise, the  changes  should  not  be  limited  to  the  blood 
but  should  include  the  other  tissues  as  well.  The 
subdivision  of  acidoses  into  compensated  and  un- 
compensated and  into  relative  and  absolute  types  is  not 
particularly  logical  nor  helpful.  Sharply  localized  ac- 
cumulations of  acid  which  do  not  produce  any  systemic 
effect  should,  at  least,  be  carefully  distinguished  from 
generalized  metabolic  disturbances  and  preferably  they 
should  not  be  considered  as  an  acidosis. 

The  transition  from  the  normal  to  a  state  of  acidosis 
is  quantitative  rather  than  qualitative  in  its  character. 
By  virtue  of  the  physiological  constancy  of  the  reserve 
supply  of  fixed  bases  this  transition  may  be  readily 
detected  by  determining  the  tolerance  to  bicarbonate. 


VII 

OCCURRENCE  OF  ACIDOSIS 

In  considering  the  occurrence  of  acidosis,  it  is  advan- 
tageous to  separate  the  conditions  in  which  it  appears 
into  two  groups,  namely,  (1)  those  diseases  in  which  it 
may  become  sufficiently  marked  to  produce  definite 
clinical  symptoms,  and  (2)  those  conditions  in  which  it 
is  so  mild  that  it  can  be  detected  only  by  laboratory 
procedures.  Such  a  division  at  once  segregates  the 
miscellaneous  group  of  cases  in  which  definite  but  in- 
consequential signs  occur.  The  diseases,  in  which  the 
development  of  clinical  symptoms  is  characteristic,  are 
few  in  number;  for  many  years  it  was  assumed  that  all 
forms  depended,  in  their  ultimate  analysis,  upon  a 
disturbance  of  the  carbohydrate  metabolism.  As  re- 
cently as  1907,  von  Nborden  pointed  out  that  it  is  only 
in  diabetes  that  definite  acidosis  has  been  established. 
At  this  time  the  possibility  of  acidosis  in  nephritis  had 
only  been  suggested  even  in  the  stage  of  uraemia,  except 
in  so  far  as  a  slight  starvation  acidosis  might  appear. 
Recently,  however,  it  has  been  established  that  extreme 
acidosis  may  develop,  not  only  in  nephritis,  but  also  in 
one  other  condition:  Howland  and  Marriott36  have 
proven  that  a  typical  and  often  fatal  form  develops  in 
some  of  the  so-called  food  intoxications  of  children. 

In  the  nephropathies,  it  is  important  to  note  that 
acidosis  does  not  occur  in  all  types  of  kidney  lesions. 
In  the  frankly  parenchymatous  type,  no  evidence  of 
acidosis  has  been  obtained.  Likewise,  in  the  early 
stages  of  the  chronic  interstitial  and  arteriosclerotic 

48 


OCCURRENCE  OF  ACIDOSIS  49 

types,  the  signs  of  acidosis  are  lacking,  but  they  develop 
in  proportion  as  the  lesions  progress,  becoming  very 
pronounced  in  the  stage  of  uraemia.  Indeed,  before  the 
development  of  uraemia,  an  advanced  acidosis  usually 
appears  in  cases  of  chronic  diffuse  nephritis,  in  primarily 
contracted  kidneys,  and  in  the  acute  nephritides.  As 
far  as  we  know  at  present,  one  would  expect  definite 
acidosis  in  any  case  of  infectious  disease  in  which  a 
severe  acute  nephritis  develops.  The  one  most  striking 
instance,  however,  is  Asiatic  cholera,  for  there  is  no 
other  infection  in  which  critical  renal  lesions  develop  in 
such  a  high  percentage  of  cases. 

Very  typical  clinical  signs  of  acidosis  may  develop  in 
one  other  condition,  namely,  in  advanced  lesions  of  the 
liver,  more  especially  in  the  atrophic  cirrhoses.  These 
cases,  at  least  those  which  present  symptoms  of  acidosis, 
are  not  very  common  and  they  have  been  studied  but 
very  little. 

It  is  often  considered  that  acidosis  frequently  accom- 
panies febrile  conditions.  Fridericia  and  Olsen  37  from 
the  examination  of  the  alveolar  air  have  reported  mod- 
erate lowering  of  the  carbon  dioxide  tension.  In  a  case 
of  erysipelas  with  a  temperature  of  38.9°  C,  values 
as  low  as  31  millimeters  were  found;  occasionally, 
though,  in  this  and  other  infections  the  lowering  was 
by  no  means  constant.  These  results,  though  sugges- 
tive, can  hardly  be  accepted  as  proof  of  acidosis  without 
the  confirmatory  evidence  of  other  methods;  in  any 
case  it  would  seem  to  be  a  rather  inconstant  phenome- 
non. Of  the  febrile  conditions  studied  by  Walker  and 
Frothingham  15  the  most  definite  lowering  occurred  in 
acute  rheumatic  fever,  a  condition  in  which  there  are 
other  definite  evidences  of  acidosis. 


50  THE  PRINCIPLES  OF  ACIDOSIS 

Barcroft 38  finding  a  diminution  in  the  carbon  dioxide 
of  the  alveolar  air  at  high  altitudes  assumes  that  there 
is  also  a  diminution  of  carbonates  in  the  blood.  This 
indication  of  acidosis  was  supplemented  by  titrating 
whole  blood  with  standard  acid  till  the  haemoglobin 
began  to  precipitate  using  this  reaction  as  an  end  point. 
The  relationship  of  these  changes  to  acidosis  is  not  yet 
fully  determined. 

Considerable  attention  has  been  directed  to  the  study 
of  acidosis  in  recent  years.  However,  one  would  hardly 
expect  to  find  many  more  diseases  in  which  typical 
fatal  acidosis  develops  as  a  common  occurrence.  A 
survey  of  the  long  list  of  diseases  prevalent  in  the 
tropics  fails  to  reveal  any  additional  conditions  which 
might  be  expected  to  reveal  a  significant  degree  of  aci- 
dosis, except  as  it  is  associated  with  secondary  anaemias 
and  the  acute  nephritides.  Even  severe  anaemias  have 
not  yet  been  shown  to  produce  acidosis  of  high  grade. 
Since  the  clinical  symptoms  of  advanced  cases  are  so 
easily  recognizable,  it  would  seem  unlikely  that  any 
extreme  conditions  had  been  overlooked,  even  when 
masked  by  complicating  factors.  Indeed  in  the  nephrop- 
athies and  in  the  diseases  of  children,  the  possibility 
of  acidosis  had  been  suspected  for  a  long  period,  on  ac- 
count of  the  clinical  symptoms.  These  cases  did  not 
conform,  however,  to  the  ordinary  diabetic  acidosis 
and  it  has  been  necessary  to  develop  new  laboratory 
methods  for  the  final  establishment  of  the  existence  of 
acidosis  in  them.  Although  there  are  no  indications 
that  any  outspoken  acidoses  have  escaped  attention, 
the  possibility  remains  that  somewhat  different  forms 
may  yet  be  discovered.  For  example,  there  is  very 
little  evidence,  at  present,  as  to  the  effect  of  a  long- 


OCCURRENCE  OF  ACIDOSIS  51 

standing  moderate  grade  of  acidosis.  It  is  not  incon- 
ceivable that  an  extremely  chronic  acidosis,  while  of  no 
consequence  per  se,  might,  nevertheless,  constitute  a 
predisposing  factor  in  association,  for  example,  with 
other  disturbances  of  nutrition.* 

The  milder  grades  of  acidosis  may  develop  and  per- 
sist for  a  short  time  in  a  variety  of  conditions  though 
there  is  apparently  a  tendency  both  among  clinical  and 
laboratory  workers  to  exaggerate  the  ease  with  which 
slight  acidosis  may  occur.  Thus,  in  the  wards  of  an 
ordinary  general  clinic,  one  would  not  expect  to  find 
cases  with  an  increase  in  soda  tolerance  to  even  twenty 
or  thirty  grams,  except  in  certain  fairly  well  recognized 
conditions.  One  should  mention,  more  especially,  acute 
rheumatic  fever,  advanced  cachexias  and  severe  anae- 
mias. Preliminary  investigations,  however,  indicate 
that  acidosis  does  not  develop  in  more  than  perhaps 
one-fifth  of  the  severe  primary  and  secondary  anaemias, 
and  even  then  it  is  usually  of  very  low  grade,  the  toler- 
ance to  bicarbonate  seldom  being  more  than  twenty  or 
thirty  grams. 

At  present,  several  workers  are  investigating  the  pos- 
sibility that  acidosis  may  play  some  role  in  the  untoward 
symptoms  following  general  anaesthesia.  Crile,40  in  his 
views  concerning  the  increase  in  the  acidity  of  the  blood 
in  anesthesia,  in  emotional  states  and  in  exertion,  de- 
parts widely  and  radically  from  the  accepted  teachings 
of  the  theory  of  neutrality  regulation. 

The  occurrence  of  acidosis  in  renal  and  cardiorenal 
disease  has  naturally  led  to  an  attempt  to  explain  in  this 

*  During  the  course  of  investigations  relating  to  this  subject  Steenbock, 
Nelson  and  Hart 39  draw  the  tentalative  conclusion  "  that  natural  acid  rations, 
if  otherwise  satisfactory,  are  as  effective  for  growth  or  reproduction  as  those 
of  basic  character." 


52  THE  PRINCIPLES  OF  ACIDOSIS 

way  the  dyspnoea  of  pure  cardiac  cases.  Porges, 
Leimdorfer  and  Markovici 18  found  a  low  carbon  dioxide 
content  of  the  alveolar  air  in  uncomplicated  cardiac 
cases.  This  evidence  is  suggestive  but  it  is  not  sup- 
ported by  other  tests  for  acidosis.  Peters  70  has  found 
an  unusual  discrepancy  in  the  relationship  between  the 
carbon  dioxide  content  of  the  alveolar  air  and  the 
venous  blood,  the  alveolar  air  showing  a  low  content 
in  contrast  to  the  high  values  found  in  the  blood.  In 
my  own  work,  four  completely  decompensated  cardiac 
cases  showed  no  change  in  the  reaction  of  their  serum 
to  phenolphthalein.  The  evidence  at  hand  does  not 
point  toward  the  existence  of  acidosis  in  uncomplicated 
cardiac  cases. 


VIII 

THERAPY 

As  regards  the  therapy  of  acidosis,  it  is  intended  to 
consider  here  only  the  use  of  alkalies,  though  obviously 
the  ideal  treatment  would  consist  in  removing  the  cause 
of  the  acidosis.  At  first  thought,  it  would  seem  plausi- 
ble to  suppose  that  the  relief  of  symptoms  in  diabetic 
coma,  which  follows  the  injection  of  massive  doses  of 
alkali,  is  due  to  neutralization  of  acid.  On  the  contrary, 
however,  no  free  acid  is  present  and  the  injected  alkali 
is  stored  as  such  in  the  body.  The  symptom  of  air 
hunger  is  due  not  to  the  presence  of  acid  but  to  the  loss 
of  carbonates  from  the  body.  The  injected  carbonates 
relieve  air  hunger  only  in  so  far  as  they  persist  in  the 
body  as  carbonates  and  function  as  such  in  carrying 
carbon  dioxide.  If  they  are  neutralized  shortly  after 
injection  by  newly  formed  acid,  then  the  relief  of  symp- 
toms does  not  occur,  or,  at  most,  is  only  very  transient.* 

The  general  effect  of  alkalies  in  the  acidosis  of  dia- 
betic coma  has  been  studied  clinically  over  a  long  period 
of  years  and  the  behavior  of  these  cases  is  well  under- 
stood. The  acidosis  of  renal  disease  arises  in  a  different 
manner  from  that  of  diabetes;    though  the  condition 

*  Confusion  on  this  point  might  readily  arise  from  von  Noorden's  discus- 
sion of  the  subject;  in  his  monograph  on  acid-intoxication  the  administra- 
tion of  alkalies  is  advised  in  diabetic  acidosis  in  order  to  combine  with  the 
acids,  to  disintoxicate  the  poisonous  acids  and  to  prevent  their  accumula- 
tion in  the  blood. 51b.  This  impression  however  is  partially  corrected  in  other 
portions  of  the  monograph  in  which  it  is  emphasized  that  /3-oxybutyric  acid 
is  non-toxic  and  produces  its  effects  by  virtue  of  its  acid  character.610 

53 


54  THE  PRINCIPLES  OF  ACIDOSIS 

is  fundamentally  the  same  in  its  general  principles, 
there  is  a  distinct  difference  between  the  nephritic  and 
diabetic  cases  as  regards  their  response  toward  alkaline 
therapy. 

The  question  of  the  advisability  of  treating  the  acido- 
sis of  nephritis  is  a  somewhat  complicated  subject,  and 
it  will  be  simpler  to  consider  the  acute  and  chronic 
types  separately.  For  the  study  of  acute  nephritis 
there  is  no  infectious  disease  which  furnishes  such  an 
important  opportunity  as  Asiatic  cholera..  The  per- 
centage of  fatal  cases  of  uraemia  is  not  only  very  high 
(average  15  per  cent)  but  they  occur  with  considerable 
regularity.  Moreover,  acute  nephritis  develops  in 
practically  all  severe  cases  which  live  till  the  stage  of 
reaction  is  reached.  One  has,  therefore,  the  opportunity 
to  study  the  effect  of  prophylactic  measures  before  the 
onset  of  nephritis,  and  of  therapeutic  measures  in  the 
stage  of  acute  nephritis  and  in  uraemia.  In  certain 
respects,  therefore,  the  conditions  are  almost  ideal  for 
a  crucial  clinical  test  of  the  therapeutic  value  of  alka- 
lies. The  disappointing  results  of  the  treatment  of 
acidosis  as  it  occurs  in  the  temperate  zones  has  been 
advanced  from  time  to  time  as  an  argument  against  the 
theory  of  acidosis  and  has  been  a  source  of  delay  in  the 
development  and  acceptance  of  this  theory.  Indeed  it 
is  so  rare  to  obtain  permanent  benefit  that  it  seems 
worth  while  to  consider  the  treatment  of  the  acidosis 
of  cholera  in  some  detail. 

The  effect  of  massive  doses  of  bicarbonate  was  tested 
by  myself  in  a  small  epidemic  of  cholera  occurring  in 
Manila.21  In  the  study  of  193  cases,  111  of  which  re- 
ceived special  treatment,  satisfactory  evidence  was  ob- 
tained that  fatal  uraemia  could  be  prevented  provided 


THERAPY 


55 


injections  of  alkali  were  commenced  either  during  the 
stage  of  collapse,  or  even  after  an  outspoken  nephritis 
had  developed,  but  before  a  typical  uraemia  had  ap- 
peared. In  a  subsequent  epidemic  comprising  a  study 
of  only  44  cases,  a  similar  result  was  obtained.  The 
cases  of  the  two  epidemics  were  divided  into  two  parallel 
series  in  which  one  group  received  alkaline  therapy,  and 
the  other,  neutral  salt  solution.  The  final  results  ob- 
tained in  the  two  epidemics  were  as  follows: 


Treatment 

No.  of 
cases 

Deaths  in 
uraemia 

Total  no. 
of  deaths 

Total  no. 
recoveries 

Bicarbonate  (or  Acetate) . 

78 
77 

12 
1* 

49 
32 

29 
45 

The  conclusions  in  regard  to  the  elimination  of  urae- 
mia, as  a  cause  of  death  by  the  use  of  bicarbonate,  are 
not  based  upon  the  percentages  in  the  preceding  outline 
but  upon  the  change  in  the  course  of  the  disease  pro- 
duced by  alkaline  therapy.  Patients  receiving  bicar- 
bonate during  the  period  of  collapse  did  not  develop 
severe  uraemia  during  the  stage  of  reaction. 

Patients  admitted  in  the  period  of  reaction,  even 
though  they  had  had  complete  suppression  of  urine  for 
several  days,  voided  freely  after  massive  injections  of 
bicarbonate.    Such  patients  sometimes  made  an  unin- 

*  This  was  an  apparently  mild  case.  No  bicarbonate  was  given  on  ad- 
mission but  30  grams  of  sodium  acetate  were  injected  —  an  inadequate 
amount  of  alkali  yielding  salt.  The  unusually  high  death  rate  in  this  group 
from  collapse  is  due  chiefly  to  the  large  number  of  cases  admitted  in  an  al- 
most moribund  condition  in  the  first  epidemic.  In  the  second  epidemic,  of 
the  22  cases  treated  with  alkali,  there  were  4  deaths  from  collapse  and  none 
from  uraemia;  of  the  same  number  treated  with  Ringer's  solution  there  were 
5  deaths  from  collapse  and  4  with  definite  signs  of  uraemia. 


56  THE  PRINCIPLES  OF  ACIDOSIS 

terrupted  recovery;  those  who  succumbed  did  not  die 
of  uraemia.  Patients  admitted  in  advanced  uraemia 
with  complete  suppression  of  urine  voided  freely  after 
liberal  injections  of  bicarbonate  but  none  of  these  cases 
recovered.  They  usually  lived  several  days,  becoming 
much  clearer  mentally  and  resting  much  more  com- 
fortably than  under  morphine  treatment. 

Some  of  the  individual  cases  were  of  especial  interest. 
One  patient  was  admitted  after  an  illness  of  two  and  a 
half  days.  The  symptoms  of  the  stage  of  collapse,  such 
as  the  cyanosis,  the  quick  shallow  respiration,  the  low 
blood  pressure  with  a  rapid,  feeble  pulse  and  the  diar- 
rhoea, had  been  replaced  by  the  characteristic  signs  of 
the  stage  of  reaction.  The  cheeks  were  flushed  and  the 
mucous  membranes  were  bright  pink  in  color;  respira- 
tion was  natural.  The  pulse  was  full  and  bounding, 
the  blood  pressure  measuring  175  millimeters  of  mer- 
cury. Constipation  had  already  set  in.  The  suppres- 
sion of  urine  had  been  complete  since  the  onset  of  the 
disease.  Thirty  grams  of  sodium  bicarbonate  were  in- 
jected intravenously,  the  tension  of  the  pulse  diminished 
and  after  ten  hours  the  blood  pressure  had  fallen  to  135 
millimeters  of  mercury.  Sixteen  hours  after  the  injec- 
tion, the  secretion  of  urine  commenced.  Without  the 
use  of  any  additional  bicarbonate,  the  amount  of  urine 
increased  rapidly  and  a  prompt  recovery  followed. 

In  another  case,  anuria  had  persisted  for  three  days. 
Secretion  of  urine  finally  commenced  eighteen  hours 
after  several  injections  of  bicarbonate,  amounting  in  all 
to  ninety  grams.  The  lesions  of  the  kidney  were  so  ad- 
vanced that  the  normal  pigments  were  entirely  sup- 
pressed when  the  first  specimen  of  urine  was  passed,  the 
sample  being  water-clear.     A  second  specimen  a  few 


THERAPY  57 

hours  later  contained  a  trace  of  pigment  and  the  third 
specimen  was  straw-colored.    This  patient  made  an  un- 
interrupted recovery  without  any  additional  injections. 
In  ascribing  these  results  to  the  effect  of  bicarbon- 
ate, the  most  pertinent  question  that  suggests  itself  is 
whether   the  anuria   of   these   cases   would   not  have 
yielded  to  injections  of  neutral  salt  solution  or  other 
therapy.     The  striking  characteristic  of  these  cases  is 
that   although   the   anuria  may   yield   spontaneously, 
there  is  no  form  of  therapy  which  can  be  depended  upon 
to  start  the  secretion  of  urine.    Injection  of  neutral  fluid 
can  be  continued  till  oedema  of  the  base  of  the  lungs 
sets  in,  without  any  urine  being  secreted.     The  effect 
of  bicarbonate  is  therefore  very  striking  since  at  practi- 
cally any  period  during  the  stage  of  reaction  or  even  of 
uraemia,  massive  injections  will  cause  a  secretion  of 
urine.    Moreover,  a  polyuria  often  develops  promptly 
in  contrast  to  the  scanty  secretion  of  the  cases  treated 
with  normal  saline.    Furthermore,  there  was  only  one 
instance  in  which  complete  suppression  of  urine  for  a 
period  of  two  days  did  not  eventually  prove  to  be  fatal 
in  the  series  treated  with  salt  solution,  whereas  seven 
cases  under  alkaline  therapy  recovered  after  an  anuria 
of  two  days'  duration;    in  a  single  instance  recovery 
took  place  after  three  days  of  total  suppression. 

This  therapeutic  action  has  also  been  confirmed  in  a 
large  measure  by  Rogers  and  Shorten.41  In  a  series  of 
225  cases,  treated  in  1915  with  alkalies,  the  death  rate 
from  uraemia  was  2.7  per  cent,  as  compared  with  11 
per  cent  in  1914,  8.5  per  cent  in  1913  and  14  per  cent  in 
1912.  Massive  injections  of  bicarbonate  were  used,  10 
to  96  grams  as  a  rule  (160  to  1440  grains),  and  in  one 
case  about  150  grams  (2240  grains).    The  reaction  of 


58  THE  PRINCIPLES  OF  ACIDOSIS 

the  urine  is  not  reported.  The  observation,  therefore, 
that  the  urine  remains  acid  after  large  injections  of 
alkali  remains  unconfirmed.  One  would  like  to  think 
that  the  urine  remained  acid  in  all  of  these  patients  but 
this  is  not  probable  in  view  of  the  results  obtained  in 
Manila.  These  cases,  however,  do  support  the  conclu- 
sions regarding  the  clinical  effect  of  bicarbonate,  not- 
withstanding the  fact  that  several  cases  died  in  uraemia. 
Three  of  these  are  readily  explained  since  they  were  ad- 
mitted in  uraemia.  As  regards  the  others,  the  treatment 
followed  by  Rogers  and  Shorten  differs  in  several  impor- 
tant respects  from  that  which  was  employed  in  my  own 
series.    The  main  points  of  difference  are  as  follows: 

1.  The  injection  of  bicarbonate  was  begun  later  in 
the  course  of  the  disease,  patients  admitted  in  collapse 
receiving  first  a  hypertonic  solution  of  sodium  chloride. 
The  subsequent  injections  consisted  first  of  a  strong  solu- 
tion of  sodium  bicarbonate  2  per  cent,  and  sodium 
chloride  followed  by  a  hypertonic  solution  of  sodium 
chloride.  In  contrast  to  this  regime  it  is  preferable  to 
begin  with  prophylactic  injections  of  alkali  before  the 
symptoms  of  acidosis  appear.  As  was  shown  by  Shaklee 
and  myself  42  the  stage  of  collapse  can  be  handled  very 
satisfactorily  with  a  one-half  per  cent  solution  of  bicar- 
bonate made  isotonic  with  Ringer's  solution,  in  as  far 
as  the  presence  of  bicarbonates  will  permit  the  calcium 
to  remain  in  solution.  This  is  theoretically  and  practi- 
cally an  improvement  on  the  use  of  hypertonic  sodium 
chloride.  McLaughlin  and  myself 43  found  no  value 
in  the  use  of  hypertonic  sodium  chloride  solutions  in  the 
treatment  of  cholera  as  compared  with  normal  saline. 

2.  In  the  stage  of  reaction  larger  injections  of  bicar- 
bonate should  be  used  omitting  the  sodium  chloride. 


THERAPY  59 

The  practice  of  flooding  the  body  with  a  large  excess  of 
sodium  ions  is  not  to  be  commended. 

3.  The  injection  of  bicarbonate  freely  into  the  blood 
stream  is  not  permissible  unless  the  reaction  of  the  urine 
is  recorded.  Observations  on  the  blood  are  valuable 
but  they  are  not  sufficiently  accurate  to  determine  the 
point  at  which  the  injection  of  bicarbonate  must  be 
discontinued.  It  is  not  permissible  to  use  massive  in- 
jections of  alkali  intravenously  after  the  urine  has  be- 
come alkaline. 

It  should  be  noted  that  Rogers  does  not  stand  alone 
in  his  recommendation  of  the  use  of  sodium  salts  only. 
Wherry  44  likewise  recommends  a  rather  concentrated 
alkaline  solution  composed  of  the  chloride  and  carbon- 
ate of  sodium  for  the  treatment  of  cholera.  The  im- 
portance of  calcium  salts  and  the  value  of  a  proper 
balance  of  the  various  salts  in  the  blood  has  been  ade- 
quately established.  Busquet  and  Pachon 45  found 
that  salts  which  precipitate  calcium  are  deleterious  in 
their  action  on  the  heart.  Loeb  46  showed  that  the 
precipitation  of  calcium  salts  gives  rise  to  muscular 
tremors  and  twitchings.  The  important  relationship 
between  calcium  salts  and  tetany  has  been  established 
by  MacCallum  47  and  his  associates.  Accordingly  it 
seems  advisable  to  employ  calcium  and  avoid  too  great 
an  excess  of  sodium  in  the  treatment  of  cholera. 

The  role  of  acidosis  in  cases  of  acute  nephritis  occur- 
ring in  the  temperate  zone  has  been  studied  very  little 
indeed.  It  is  entirely  reasonable  to  suppose  that  therapy 
with  alkalies,  if  it  is  commenced  sufficiently  early,  would 
tide  these  patients  over  the  period  of  grave  renal  crisis. 
In  many  instances,  however,  the  original  cause  of  the 
renal  lesions,   e.  g.,   the    septicaemias    of   Micrococcus 


60  THE  PRINCIPLES  OF  ACIDOSIS 

lenta,  would  persist  with  serious  manifestations  in  con- 
trast to  the  promptness  with  which  many  patients  re- 
cover from  infection  with  cholera. 

The  effect  of  prophylactic  measures  and  the  therapy 
of  acute  nephritis  is  naturally  much  more  hopeful  than 
the  treatment  of  advanced  chronic  conditions.  The 
action  of  alkalies  in  chronic  nephritis  was  tested  upon 
some  cases  occurring  in  Baltimore.  In  a  few  cases  of 
uraemia  developing  in  the  course  of  a  long-standing  dif- 
fuse nephritis,  a  definite  clinical  effect  was  produced  by 
massive  injections  of  bicarbonate,  as  much  as  160 
grams  being  used  in  one  instance.  The  air  hunger  was 
partially  relieved,  the  coma  diminished,  patients  were 
made  distinctly  more  comfortable,  and  in  some  in- 
stances, the  secretion  of  urine  improved.  The  relief, 
however,  was  only  partial  and  was  very  transitory, 
lasting  not  more  than  two  or  three  days.  In  two  cases 
which  may  be  designated  as  preuraemic,  the  mental 
condition  cleared  up  promptly  after  injection,  the 
dyspnoea  disappeared  and  the  patients  remained  in  good 
condition  during  the  few  succeeding  weeks  in  which 
they  were  under  observation  before  discharge  from  the 
hospital.  There  was  still  another  case  in  which  the  be- 
havior proved  to  be  instructive.  This  patient  when  at 
rest  in  bed  had  slight  dyspnoea  and  though  perfectly 
clear  he  became  fatigued  mentally  rather  easily.  This 
case  received  120  grams  of  bicarbonate  intravenously; 
his  respiration  became  natural  and  mentally  he  became 
distinctly  more  alert.  He  also  noticed  this  change  and 
expressed  some  surprise  at  his  previous  apathy. 

Even  in  fatal  uraemia  alkali  therapy  is  of  value,  in 
that  it  is  the  only  agent  that  will  relieve  air  hunger  and 
also  it  is  more  effective  than  morphine  in  controlling 
restlessness. 


THERAPY  61 

It  is  hardly  necessary  to  caution  against  the  inter- 
pretation that  all  dyspnoea  of  renal  disease  could  be 
relieved  by  therapy  with  alkalies.  Chronic  nephritis 
becomes  such  a  complicated  picture  that  simple  air 
hunger  in  uraemia  is  perhaps  the  exception  rather 
than  the  rule. 

Coming  now  to  the  earlier  cases  of  chronic  interstitial 
nephritis,  without  any  symptoms  of  acidosis,  it  will  be 
seen  that  the  determination  of  the  clinical  effect  of  re- 
lieving this  acidosis  is  naturally  a  very  difficult  problem. 
Perhaps  the  best  way  of  approach  would  be  to  follow 
large  groups  of  cases  over  a  long  period  of  years.  Un- 
fortunately, there  are  no  clear  data  available  in  regard 
to  whether  a  long-standing  chronic  acidosis  would  have 
any  effect  upon  general  health,  upon  metabolism  and, 
more  particularly,  upon  the  progress  of  the  renal  lesions. 
It  is  not  impossible  that  the  early  attention  to  acidosis 
might  have  a  favorable  influence  on  the  course  of  the 
nephritis.  The  findings  in  chronic  nephritis,  in  acute 
nephritis,  and  in  uraemia  would  fully  justify  one  in 
investigating  the  effect  of  relieving  the  earlier  stages 
of  acidosis.  This  would  involve  the  administration  of 
moderate  quantities  of  bicarbonate,  a  procedure  which 
is  not  objectionable  even  in  nephritis  when  we  consider 
the  importance  of  these  salts  in  normal  metabolism  for 
the  function  of  internal  respiration.  The  necessity  of 
this  function  is  best  illustrated  by  observing  the  effect 
of  the  gradual  removal  of  the  carbonates  from  the  body. 
Data  upon  man  were  obtained  by  observing  the  effect 
of  varying  degrees  of  depletion  of  bicarbonate  that  oc- 
cur spontaneously  in  chronic  nephritis,  i.  e.,  the  clinical 
symptoms  in  a  group  of  cases  were  studied  and  the 
degree  of  depletion  was  subsequently  measured  by  deter- 


62  THE  PRINCIPLES  OF  ACIDOSIS 

mining  the  tolerance  to  bicarbonate.  In  patients  who 
were  not  taking  active  exercise  a  deficit  of  even  40  or  50 
grams  of  sodium  bicarbonate  was  not  accompanied  by 
any  clinical  signs.*  This  constitutes  a  moderately  wide 
margin  of  safety  in  the  supply  of  bases  which  the  body 
possesses.  With  a  deficit  of  75  to  100  grams  distinct 
dyspnoea  was  observed  in  patients,  sometimes  after 
very  moderate  exercise  and  even  in  cases  at  rest  in  bed. 
An  individual  with  a  deficit  of  110  grams  exhibited  in 
addition  to  dyspnoea  a  moderate  degree  of  mental  con- 
fusion. As  the  tolerance  rose  to  a  deficit  of  150  to  200 
grams,  patients  developed  uraemia  with  definite  air 
hunger  and  coma.  A  deficit  beyond  200  grams  of  bi- 
carbonate is  usually  followed  comparatively  soon  by 
death.  Apparently  life  is  able  to  continue  for  a  time 
with  only  a  minimal  amount  of  fixed  bases  in  the  blood. 
Accordingly  it  appears  that  the  adult  possesses  not  very 
much  more  than  200  grams  of  sodium  bicarbonate  or 
its  equivalent  in  a  form  available  for  the  function  of 
respiration.  In  other  words  the  total  supply  is  at  least 
a  figure  of  that  order  of  magnitude. 

The  treatment  of  these  cases  relieved,  in  part  at 
least,  some  of  the  supposedly  toxic  symptoms  of  urae- 
mia, namely,  the  dyspnoea  and  the  mental  confusion. 
Thus  it  is  seen  that  at  least  part  of  the  picture  of  urae- 
mia is  due,  not  to  the  presence  of  a  foreign  toxin,  but  to 
the  loss  of  a  normal  constituent  of  the  blood  and  tis- 
sues. In  the  practice  of  bleeding  for  the  relief  of  uraemia, 
it  must  be  remembered  that,  if  this  procedure  removes 

*  If  one  accepts  Fischer's  theories  of  nephritis  then  the  albuminuria  of 
these  cases  might  be  considered  as  one  of  the  signs  of  this  deficit  of  bicar- 
bonate. If  this  discussion  the  only  clinical  signs  under  consideration  are  the 
respiration,  the  color  of  the  mucous  membranes  and  the  mental  condition, 
i.  e.,  the  generally  accepted  clinical  evidences  of  acidosis. 


THERAPY  63 

toxins  in  the  blood,  it  also  depletes  the  body  still  fur- 
ther in  the  carbonates  which  are  already  seriously 
reduced.  This  disadvantage,  of  course,  could  be  readily 
remedied  by  injection  of  carbonates. 

In  conclusion  we  may  note  that  the  depletion  in  al- 
kalies occurs  comparatively  early  in  chronic  interstitial 
and  diffuse  nephritis.  If  it  is  unchecked,  it  goes  on  to 
the  point  where  it  produces  marked  discomfort  to  the 
patient,  and  eventually,  it  sometimes  becomes  the  im- 
mediate cause  of  death.  If  we  postpone  treatment  until 
clinical  symptoms  of  uraemia  appear,  then  it  may  re- 
quire comparatively  heroic  intravenous  injections  to 
reduce  the  acidosis,  whereas,  this  can  be  easily  accom- 
plished in  the  early  stages  by  the  ingestion  of  a  little 
bicarbonate.  One  hopeful  point  in  the  treatment  is  that, 
in  contrast  to  diabetes,  the  effect  of  a  course  of  bicar- 
bonate therapy  in  the  acidosis  of  nephritis  was  shown 
to  last  for  a  comparatively  long  time,  even  weeks  or 
months.  Thus  in  general,  it  would  seem  plausible  to 
make  a  practice  of  occasionally  giving  sufficient  alkali 
by  mouth  to  bring  the  urine  down  to  a  reaction  that  is 
neutral  or  alkaline  to  litmus.  A  priori,  it  would  seem 
inadvisable  to  keep  the  urine  constantly  alkaline.  Cer- 
tainly it  seems  logical  to  assume  that  the  maintenance 
of  the  carbonate  content  of  the  body  at  its  normal  level 
would  not  have  any  unfavorable  effect.  Moreover,  in 
the  injection  of  massive  doses  of  bicarbonate  in  uraemia 
(150  grams  in  40  hours),  no  effect  was  seen  in  regard  to 
oedema.  In  cases  where  oedema  was  present  previous 
to  the  injection,  the  amount  of  the  oedema  was  neither 
increased  nor  diminished;  in  cases  without  oedema, 
none  was  produced  by  the  injection.  This  result 
is  not  in  agreement  with  Fischer's  theories  of  the  cau- 


64  THE  PRINCIPLES  OF  ACIDOSIS 

sation  of  oedema  by  acids  and  its  relief  by  alkaline 
therapy. 

In  contrast  to  this  difficulty  of  determining  the  clini- 
cal effect  of  alkaline  therapy  in  early  chronic  cases,  it 
is  extremely  easy  to  detect  the  immediate  change  pro- 
duced in  the  blood  and  urine  by  the  injection  of  alkalies. 
Thus  with  massive  injections,  the  carbon  dioxide  ten- 
sion of  the  alveolar  air  rises  rapidly.  Likewise  the 
titratable  alkalinity  and  the  carbon  dioxide  content 
of  the  blood  increase  rapidly.  When  these  factors  have 
been  rendered  normal,  a  small  additional  injection  of 
bicarbonate  will  render  the  urine  alkaline.  In  nephritic 
cases  with  suppression,  the  total  volume  of  the  urine 
often  increases  remarkably.  In  diabetic  acidosis  the 
ammonia  output  falls  rapidly  but  the  excretion  of  ace- 
tone and  the  "  acetone  bodies  "  continues  and  often 
increases  owing  to  the  flushing  out  of  the  tissues.  For- 
tunately for  clinical  purposes,  it  is  not  at  all  necessary 
to  control  the  administration  of  bicarbonate  by  the  de- 
termination of  all  of  these  factors.  In  view  of  the 
demonstration  that  alkali  is  excreted  readily,  even  in 
advanced  renal  disease,  it  is  sufficient  to  observe  the 
reaction  of  the  urine  to  litmus. 

Fischer  has  recommended  the  use  of  large  quantities 
of  sodium  carbonate  and  sodium  chloride  to  be  given  in 
all  forms  of  nephritis  until  there  is  improvement  in 
clinical  symptoms.  Hogan  and  others,  acting  on  this 
advice,  have  reported  favorable  results.35  Subse- 
quently, Fischer  48  has  modified  this  suggestion  recom- 
mending that  the  carbonate  be  given  only  until  the 
urine  becomes  persistently  neutral  to  litmus.  This 
modification  would  eliminate  many,  if  not  all,  of  the 
frankly  parenchymatous  cases  from  treatment  by  alkali, 


THERAPY  65 

since  they  often  respond  with  an  alkaline  urine  after  a 
small  dose  of  alkali.  Very  unfortunately,  in  the  cases 
cited  by  Fischer,35  no  data  are  given  in  regard  to  the 
reaction  of  the  urine;  consequently,  one  is  left  in  doubt 
as  to  whether  these  patients  retained  the  carbonate  for 
use  in  the  body  or  whether  it  was  promptly  excreted. 
This  information  would  be  especially  interesting  in  the 
eclamptic  cases,  since  no  one  has  yet  reported  definite 
evidence  that  there  is  a  diminution  of  alkalies  in  the 
blood  of  eclamptics  or  that  there  is  any  indication  for 
therapeutic  injection  of  alkalies.  It  seems  especially 
important  to  avoid  the  free  use  of  alkalies  in  the  frankly 
parenchymatous  types  of  nephritis  since  these  patients 
are  prone  to  react  rather  violently  to  even  small  doses 
(10  grams)  of  bicarbonate.  Likewise  the  use  of  large 
quantities  of  alkalies  is  not  permissible  except  in  those 
cases  where  it  is  definitely  known  that  a  marked  deficit 
of  carbonate  exists.  This  is  a  requirement  that  is  ex- 
tremely simple  to  fulfill.  In  the  early  cases  it  is  entirely 
justifiable  to  administer  5  grams  of  sodium  bicarbonate 
by  mouth  repeating  this  dose  every  two  or  three  hours 
till  the  urine  becomes  alkaline. 

Also,  it  seems  necessary  to  caution  against  the  unre- 
stricted use  of  the  normal  carbonate.  A  spurious  idea 
has  gained  access  to  the  literature  that  the  normal  car- 
bonate is  much  more  effective  in  relieving  acidosis  than 
the  bicarbonate.*  Two  reasons  are  assigned  for  this, 
namely,  (1)   that  the  carbonate  has  greater  neutralizing 

*  It  is  hardly  necessary  to  call  attention  to  the  fact  that  neither  the  car- 
bonate nor  bicarbonate  are  alkalies.  Normal  sodium  carbonate  is  the  neutral 
salt  of  carbonic  acid  comparable  to  sodium  sulphate  or  chloride.  However  it 
differs  markedly  from  these  in  one  respect;  on  solution  in  water,  the  carbonate 
breaks  up  and  gives  rise  to  alkali  through  dissociation  of  the  water.  Sodium 
chloride,  being  the  salt  of  a  very  strong  acid,  cannot  produce  this  effect. 


66  THE  PRINCIPLES  OF  ACIDOSIS 

power  than  the  bicarbonate  and  (2)  that  it  can  take  up 
additional  carbon  dioxide  whereas  the  bicarbonate  can- 
not. Gram  for  gram,  the  carbonate  neutralizes  much 
more  acid  than  the  bicarbonate  (1.6  times  as  much). 
However,  one  can  safely  use  a  much  stronger  solution 
of  bicarbonate  than  of  the  caustic  carbonate.  The  total 
amount  of  alkali  which  can  be  administered  is  limited, 
in  the  first  place,  by  the  amount  of  fluid  which  can  be 
injected,  and  secondly,  by  the  toxicity  of  the  alkali 
that  is  used.  This  is  very  great  for  the  caustic  carbonate 
as  compared  with  the  bicarbonate.  Thus  one  can  use  a 
dosage  of  the  bicarbonate  several  times  greater  than 
one  could  employ  of  the  carbonate  with  impunity. 
This  at  once  outweighs  any  advantage  of  the  greater 
neutralizing  property  of  the  normal  carbonate. 

As  regards  the  inability  of  the  bicarbonate  to  take  up 
more  carbon  dioxide,  this  is  only  an  apparent  disad- 
vantage. In  the  lungs,  the  bicarbonate  breaks  up 
promptly,  giving  off  carbon  dioxide,  and  then  the  re- 
sulting carbonate  is  able  to  take  up  carbon  dioxide  from 
the  tissues.  The  use  of  bicarbonate  not  only  affords  the 
body  a  convenient  source  of  normal  carbonate  which 
it  can  use  readily,  but  it  very  conceivably  furnishes  it 
in  the  form  of  a  reserve  supply  which  it  can  draw  upon 
and  convert,  only  as  rapidly  as  it  is  needed,  to  the 
normal  carbonate.  With  proper  precautions  the  ad- 
ministration of  alkalies  is  not  attended  by  danger  or 
disadvantage.  In  contrast  to  the  view  expressed  by 
Joslin  n  it  seems  to  me  that  the  replacement  of  alkalies 
in  acidosis  is  a  necessary  step  corresponding  to  the 
maintenance  of  a  proper  supply  of  food  and  liquid. 

The  investigations  of  Howland  and  Marriott  show 
that  the  therapy  of  the  acidosis  of  infantile  food  intoxi- 


THERAPY  67 

cation  agrees  closely  with  the  general  effects  of  the 
treatment  of  acidosis  in  nephritis  and  in  diabetes. 
Symptomatic  relief  may  usually  he  obtained  in  the 
severest  cases,  but  this  relief  is  only  temporary  except 
in  an  occasional  brilliant  instance  in  which  prompt 
recovery  has  been  obtained  by  the  injection  of  bi- 
carbonate. The  early  treatment  of  incipient  cases, 
however,  before  the  attack  is  fully  developed  offers 
much  more  hope.  Early  in  the  development  of  the 
subject  of  acidosis  in  children  Edsall 49  directed  atten- 
tion to  the  question  of  therapy.  By  the  liberal  use  of 
alkalies,  impending  attacks  were  avoided  and  the  acute 
underlying  symptoms  subsided  of  themselves  in  a  few 
days. 

The  simplicity  of  the  theory  of  acidosis  and  the  bril- 
liancy of  the  effect  of  treatment  in  experimental  animals 
led  to  the  hope  of  similar  results  in  clinical  medicine. 
However,  the  merely  transitory  relief  which  follows  the 
treatment  of  advanced  stages  is  a  very  discouraging 
feature.  This  failure  in  therapy  appears,  at  first  glance, 
a  little  paradoxical.  Yet  it  is  obvious  that  spontaneous 
cases  in  man  may  be  accompanied  by  fundamental  dif- 
ferences from  the  acidosis  produced  in  rabbits  by  the 
ingestion  of  mineral  acid.  The  precise  nature  of  these 
differences  has  not  yet  been  carefully  defined.  In  dia- 
betes, the  failure  of  therapy  is  advanced  as  one  of  the 
arguments  that  the  coma  is  by  no  means  due  solely  to 
acidosis.  This  view  receives  support  from  the  apparent 
occurrence  of  diabetic  coma  in  patients  who  are  free 
from  acidosis.  One  hopeful  point  in  therapy  consists 
in  the  suggestion  of  Marriott  and  Howland  50  as  to  the 
possible  relationship  in  uraemia  of  the  deficiency  of 
calcium  salts  and  the  occurrence  of  convulsions.     In 


68  THE  PRINCIPLES  OF  ACIDOSIS 

two  cases  of  typical  ureamia  Peabody  found  that  defi- 
nite though  temporary  cessation  of  muscular  twitchings 
occurred  after  the  intravenous  injection  of  calcium 
chloride.  These  preliminary  results  were  sufficiently 
suggestive  to  justify  further  observations  along  this 
line.* 

It  should  be  remembered  that  the  loss  of  carbonates 
is  accompanied  by  a  simultaneous  depletion  of  calcium, 
magnesium,  sodium  and  potassium  salts.  In  treat- 
ment, the  tendency  for  the  most  part  is  to  replace  only 
the  sodium  and  the  carbonates.  Perhaps  some  of  the 
symptoms  are  due  to  the  loss  of  calcium,  magnesium 
and  potassium  salts.  Von  Noorden  51a  does  not  admit 
that  calcium  plays  any  specific  part  in  acidosis  but 
recommends  its  administration  in  long  standing  cases  of 
acidosis. 

Osborne,  Mendel  and  Ferry  52  by  varying  the  salt  con- 
tent of  the  diet  produced  some  extremely  interesting 
results  which  may  prove  to  have  very  direct  bearing  on 
acidosis.  Rats  which  were  fed  on  a  diet  poor  in  salts 
but  otherwise  satisfactory  eventually  developed  coma. 
They  were  resuscitated  by  the  administration  of  a 
mixture  of  salts  consisting  of  calcium  and  potassium 
phosphates,  sodium  chloride  and  the  citrates  of  sodium, 
magnesium,  calcium,  and  iron. 

*  Peabody.     Personal  communication. 


IX 

DIFFERENTIAL  DIAGNOSIS 

Although  acidosis,  in  the  majority  of  instances,  is  not 
of  primary  importance  either  in  etiology  or  therapy, 
nevertheless,  it  is  sometimes  of  considerable  interest  in 
differential  diagnosis.  The  infrequency  of  acidosis  in 
parenchymatous  nephritis,  as  compared  with  chronic 
diffuse  types,  renders  it  of  value  in  the  study  of  the 
nephritides  themselves.  Indeed,  the  degree  of  acidosis 
is  of  very  definite  value  as  a  test  of  renal  function.  It 
constitutes  a  very  satisfactory  and  very  direct  test  of 
the  ability  of  the  kidney  to  excrete  an  acid  urine,  one 
of  the  several  cardinal  functions  of  this  organ.  More- 
over, except  in  parenchymatous  nephritis  the  property 
of  excreting  acid  constitutes  a  very  good  index  of  the 
general  state  of  the  other  functions  of  the  kidney.  In 
this  connection  it  is  interesting  that  the  tolerance  to 
bicarbonate  frequently  parallels  in  a  very  general  way 
the  ability  to  excrete  phenolsulphonephthalein.  In  an 
early  paper,22  the  tests  for  tolerance  to  bicarbonate 
were  looked  upon  as  being  much  less  delicate  than 
the  phenolsulphonephthalein  tests.  This  interpretation 
was  made  at  the  time  when  the  authors  of  the  'phthalein 
test  considered  it  to  be  almost  infallible.  Since  then  it 
has  been  recognized  that  parenchymatous  cases,  even 
though  severe,  usually  have  a  high  output  of  this  and 
other  dyes;  on  the  other  hand,  some  mild  nephritides 
on  a  single  test  will  show  a  low  output  although  the 
renal  function,  as  far  as  its  natural  duties  are  concerned, 

69 


70  THE  PRINCIPLES  OF  ACIDOSIS 

is  nearly  normal.  The  determination  of  the  tolerance 
to  bicarbonate  has  one  distinct  advantage  over  the 
artificial  tests  in  that  it  constitutes  one  of  the  natural 
functions  of  the  kidney  in  maintaining  normal  metab- 
olism, whereas  the  ability  to  excrete  foreign  dyes  bears 
only  an  accidental  relation  to  the  ordinary  functions  of 
this  organ.  The  continuous  separation  of  an  acid  urine 
by  the  kidney  from  an  alkaline  plasma  is  of  considerable 
consequence  to  the  organism  as  a  whole  and  the  deter- 
mination of  the  tolerance  to  bicarbonate  constitutes  a 
very  satisfactory  test  of  this  function. 

The  detection  of  acidosis  facilitates  considerably  the 
prompt  differentiation  of  diabetic  and  uraemic  coma 
from  other  types  and  also  renders  substantial  assistance 
in  the  detailed  investigation  of  the  diseases  of  the  heart, 
brain  and  kidneys.  In  considering  the  very  complex 
pictures  resulting  from  lesions  of  these  organs,  it  is 
often  inadvisable  to  attempt  a  sharp  definition  of  the 
exact  extent  to  which  the  various  organs  are  affected. 
It  is  sufficient  to  determine  whether  the  essential  feature 
is  a  lesion  affecting  primarily  the  heart,  brain  or  kidney, 
or  whether  the  picture  is  a  composite  one  in  which  no  one 
factor  predominates.  It  might  seem  that  the  general 
division  of  these  cases  could  be  made  most  appropri- 
ately on  clinical  grounds  without  the  aid  of  laboratory 
methods.  Even  in  the  cases  which  clinically  appear 
to  be  very  clear,  there  is,  however,  the  possibility, 
at  times,  of  making  a  striking  error  in  diagnosis,  at 
least  temporarily.  Under  emergency  conditions,  the 
laboratory  tests  may  be  of  value;  this  is  especially  true 
in  cases  where  a  history  is  unavailable  and  when  there 
has  been  no  opportunity  for  obtaining  a  series  of  clinical 
observations.    As  an  illustration  of  such  an  instance  a 


DIFFERENTIAL  DIAGNOSIS  71 

man,  age  45,  was  admitted  to  the  clinic  in  coma,  with 
almost  complete  suppression  of  urine.  No  history  was 
available  except  that  the  coma  was  of  twelve  hours' 
duration  and  the  patient  had  been  given  a  diagnosis  of 
chronic  nephritis  eighteen  years  previously.  On  cathe- 
terization a  few  drops  of  urine  were  obtained;  this  spec- 
imen showed  a  variety  of  casts  and  a  moderate  amount 
of  albumin.  A  liberal  secretion  of  urine  started  within 
twelve  hours.  The  casts  diminished  in  number  and 
only  a  trace  of  albumin  remained.  On  admission,  an 
examination  of  the  blood  serum  with  phenolphthalein 
showed  no  evidence  of  even  a  mild  acidosis  and  there 
was  no  increase  in  rest  nitrogen.  The  subsequent  clini- 
cal developments  confirmed  the  tentative  laboratory 
conclusion  that  this  was  not  a  case  of  uraemia.  The 
coma  persisted  for  four  days  and  then  cleared  up  very 
gradually  in  the  course  of  the  next  ten  days,  with  paraly- 
sis persisting  in  the  right  arm.  During  this  period,  the 
kidney  was  functioning  very  well  indeed,  the  evidence 
indicating  that  there  was  only  a  mild  degree  of  ne- 
phritis. It  eventually  became  clear  that  there  had  been 
a  cerebral  hemorrhage. 

As  a  further  illustration  of  this  discussion,  a  patient 
with  a  marked  mitral  insufficiency  and  slight  renal  in- 
volvement, complained  of  serious  dyspnoea  which,  at 
times,  resembled  air  hunger.  The  heart  was  compen- 
sating well,  and  although  renal  involvement  did  not 
appear  to  be  especially  serious,  the  possibility  of  urae- 
mia was  considered  on  account  of  the  dyspnoea.  There 
was  no  acidosis  present  in  this  case  and  the  dyspnoea 
eventually  proved  to  be  of  neurotic  origin. 

For  a  thorough  study  of  these  cardiorenal  and  cere- 
bral cases,  it  seems  not  unlikely  that  a  careful  examina- 


72  THE  PRINCIPLES  OF  ACIDOSIS 

tion  of  the  blood  and  urine  with  respect  to  renal  function 
and  acidosis  might  furnish  useful  information.  Indeed 
it  would  be  desirable  to  obtain  extensive  data  on  the 
occurrence  of  acidosis  in  uraemia;  although  the  degree 
varies  considerably,  nevertheless,  in  my  own  cases  and 
in  those  of  Peabody  27  at  least  a  moderate  grade  was 
constantly  present.  Although  the  entire  number  of 
patients  studied  is  not  large  it  seems  unlikely  that  any 
considerable  number  of  instances  would  be  found  in 
which  no  acidosis  occurs.  In  studying  this  question, 
it  might  be  emphasized  that  in  special  cases  there  is 
opportunity  for  considerable  divergence  of  opinion  in 
the  clinical  diagnosis  of  uraemia. 


X 

ETIOLOGY  OF  ACIDOSIS 

In  explanation  of  the  manner  in  which  acidosis  arises, 
two  distinct  causes  are  known,  namely,  defective  oxi- 
dation of  organic  acids  and  defective  elimination  of  the 
mineral  acids.  The  best  example  of  defective  oxida- 
tion occurs  in  diabetes  while  the  nephropathies  com- 
prise the  group  of  defective  elimination.  In  diabetes 
Magnus-Levy  B3  has  insisted  that  there  is  no  increased 
production  of  acids  but  rather  an  increased  accumula- 
tion. In  other  words  the  body  normally  forms  a  large 
quantity  of  acid  and  oxidizes  it  immediately;  in  diabetic 
acidosis  only  the  normal  amounts  of  acid  are  formed 
but  instead  of  being  at  once  oxidized  they  are  allowed 
to  accumulate.  A  more  correct  statement  would  be 
that  there  is  neither  an  increased  production  nor  an 
increased  accumulation  of  acid  but  that  in  health,  the 
acid  is  removed  by  oxidation  and  eliminated  as  carbon 
dioxide  from  the  lungs,  whereas  in  diabetic  acidosis,  it 
is  removed  by  neutralization  and  elimination  from  the 
kidneys. 

In  the  nephropathies,  although  no  disturbance  of 
oxidation  develops,  still  there  is  no  doubt  that  the  loss 
of  alkalies  is  due  to  neutralization  by  acid.  The  source 
of  this  acid,  however,  is  not  clear.  New  acids  might  be 
appearing  in  the  urine  or  the  acids  normally  present 
might  be  increased  in  amount.  From  the  evidence 
which  is  available  at  present,  there  is  no  need  to  assume 

73 


74  THE  PRINCIPLES  OF  ACIDOSIS 

an  increase  in  the  amount  of  normal  acids  or  the  ap- 
pearance of  a  new  acid  in  metabolism  in  nephritis.  In- 
deed, on  the  other  hand,  Henderson  and  Palmer  54  have 
even  reported  a  diminution  of  the  acidity  of  the  urine  in 
certain  severe  cases.  The  same  result  has  been  obtained 
by  Peabody.27  This  would  explain,  in  a  large  measure, 
the  depletion  of  the  blood  and  tissues  in  alkalies.  It 
becomes  necessary  to  abandon  the  view  of  von  Noor- 
den  Bld  that  diminished  elimination  of  acid  is  not  of 
practical  significance  in  the  production  of  acidosis. 
Thus,  the  normal  kidney  possesses  the  rather  striking 
function  of  excreting  acids  in  the  urine.  With  the  de- 
velopment of  nephritis  and  general  impairment  of  kid- 
ney function,  it  is  only  natural  that  the  function  of 
excreting  acid  should  suffer  also,  with  the  result  that 
acid  radicals,  which  are  ordinarily  eliminated  in  the 
urine,  would  now  neutralize  fixed  bases  of  the  blood 
before  elimination  occurs.  This  view,  that  the  acidosis 
results  from  an  impairment  of  the  kidney  function,  is 
supported  rather  strongly  by  several  facts.  In  the  first 
place,  the  degree  of  acidosis  is,  in  general,  parallel  to 
the  other  signs  of  defective  excretion  as  measured  by 
the  elimination  especially  of  sugars  and  dyes,  even  to  the 
extent  of  the  suppression  of  the  normal  pigments  of 
the  urine.  In  chronic  nephritis,  acidosis  develops  only 
gradually,  and  in  contrast  to  diabetes,  it  does  not  reach 
a  high  grade  as  long  as  the  excretion  of  acid  by  the 
kidney  is  comparatively  efficient.  Even  in  high  grades 
of  acidosis,  the  effect  of  the  injection  of  carbonates  lasts 
for  a  comparatively  long  time.  In  any  case,  therefore, 
whether  the  acid  in  nephritis  is  a  new  product  or  one  of 
the  normal  acids,  it  is  not  produced  rapidly  and  its 
neutral  salt  does  not  accumulate  in  large  quantities. 


ETIOLOGY  OF  ACIDOSIS  75 

More  direct  evidence  of  the  deficient  elimination  of 
acids  by  the  kidney  in  nephritis  has  recently  been 
brought  forth  by  Marriott  and  Howland  50  who  showed 
that  the  inorganic  phosphates  of  the  blood  are  increased 
in  those  cases  of  nephritis  in  which  acidosis  is  present. 
Since  the  alkali  reserve  of  the  blood  is  depleted  in  these 
cases,  the  natural  assumption  would  follow  that  the  kid- 
ney is  neither  able  to  excrete  the  phosphates  in  the  acid 
form  nor  after  conversion  to  basic  phosphate  by  the 
fixed  alkali.  This  brings  up  the  question  of  whether  it 
is  the  acid  radical  or  the  phosphate  group  which  gives 
rise  to  difficulty  in  excretion.  The  acidosis  of  nephritis 
does  not  rest  even  in  its  ultimate  analysis  upon  a  dis- 
turbance of  the  carbohydrate  metabolism;  it  is  not 
accompanied  by  an  increase  in  the  ammonia  output  in 
the  urine  and  no  abnormal  acids  have  as  yet  been  dis- 
covered in  the  urine.  In  these  details,  this  acidosis  con- 
stitutes a  very  different  type  from  the  classical  picture 
of  diabetic  acidosis,  though  fundamentally,  the  under- 
lying principle  in  the  two  acidoses  are  identical.  The 
position  of  the  acidosis  occurring  in  the  nephritis  of 
Asiatic  cholera  is  very  interesting  inasmuch  as  it  is 
somewhat  intermediate  between  these  two  types.  It 
conforms  to  ordinary  nephritis  in  that,  except  in  oc- 
casional instances,  there  is  no  marked  increase  in  the 
output  of  acetone  in  the  urine.  Unlike  ordinary  ne- 
phritics  and  in  conformity  with  diabetic  acidosis  there 
is  an  extremely  large  output  of  ammonia  in  the  urine. 
The  ammonia  coefficient  can  be  at  least  partially 
reduced  by  the  administration  of  bicarbonate.  No 
especial  attention  was  directed  toward  the  ammonia 
metabolism  in  these  cases  of  cholera  since,  at  the  time 
they  were  studied,  the  behavior  of  ammonia  in  the 


76  THE  PRINCIPLES  OF  ACIDOSIS 

acidosis  of  ordinary  nephritis  had  not  yet  been  inves- 
tigated. 

Thus  from  a  study  of  diabetes  and  nephritis,  we  are 
able  to  pick  out  the  fundamental  features  which  will  be 
found  in  any  acidosis  and  the  incidental  features 
which  vary  with  the  type  of  acidosis,  its  etiology,  and 
with  the  more  or  less  accidental  circumstances  ac- 
companying the  condition  of  the  individual  patient. 
Thus  in  any  outspoken  acidosis,  the  tolerance  to  bicar- 
bonate will  be  increased,  the  carbon  dioxide  content  of 
the  blood  and  alveolar  air  as  well  as  the  titratable  alka- 
linity of  the  blood  will  be  diminished.  In  death  from 
acidosis,  the  actual  alkalinity  of  the  blood  will  decrease 
slightly,  i.  e.,  the  hydrogen  ion  content  will  rise.  In 
typical  chronic  diffuse  nephritis  practically  no  other 
features  accompany  this  picture.  Of  the  incidental 
features,  there  are  only  two  of  primary  importance, 
namely,  ammonia  and  the  "  acetone  bodies."  The  out- 
put of  ammonia  in  the  urine,  once  considered  as  a  car- 
dinal sign  of  acidosis,  may  or  may  not  rise,  according 
as  to  whether  the  body  is  able  to  substitute  ammonia 
for  the  fixed  bases  in  the  neutralization  of  acids.  In 
diabetes  and  in  Asiatic  cholera,  the  ammonia  coefficient 
usually  rises;  in  ordinary  nephritis  it  remains  low.  The 
output  of  acetone  and  the  "  acetone  bodies  "  depends 
upon  whether  there  is  a  disturbance  of  carbohydrate 
metabolism.  They  ordinarily  increase  in  diabetic  acido- 
sis and  occasionally  in  any  acidosis,  merely  as  a 
starvation  phenomenon.  It  is  perhaps  worth  while  to 
present  these  features  in  tabular  form. 


ETIOLOGY  OF  ACIDOSIS 


77 


Disease  in  which  acidosis  occurs 

Evidences  of  acidosis 

Diabetes 

Ordinary  ne- 
phropathies 

Nephritis  of 
Asiatic  cholera 

"  Food  intoxi- 
cation of 
children  " 

Tolerance    to 
sodium  bicar- 
bonate 

Increased 

Increased 

Increased 

Increased 

tn 

| 

'a 

V 
■M 

~3 
a 
1 

Carbon   diox- 
ide     content 
of   blood   and 
alveolar  air 

Decreased 

Decreased 

(Decreased)  * 

Decreased 

a 

si 

§ 

■M 

a 

a 

Titratable  al- 
kalinity of  the 
blood 

Decreased 

Decreased 

(Decreased)  f 

Decreased 

GO 

a 
o 
U 

Hydrogen  ion 
concentration 
of  the  blood 

Terminal    in- 
crease 

Terminal  in- 
crease 

(Terminal  f 
increase) 

(Terminal  f 
increase) 

Clinical 
symptoms 

Present  in  ad- 
vanced stages 

Present  in  ad- 
vanced stages 

Present  in  ad- 
vanced stages 

Present  in  ad- 
vanced stages 

2     3 

"  Acetone 
bodies  " 

Increased 

Normal 

Usually  nor- 
mal 

Slightly        in- 
creased 

>  £ 

Ammonia 
output 

Increased 

Normal 

Increased 

Often 
increased 

•  Not  yet  demonstrated  for  the  alveolar  air. 

t  These  features  have  not  yet  been  demonstrated  experimentally,  but  theoretically  they 
must  occur. 

This  variation  in  the  excretion  of  acetone  and  am- 
monia in  the  different  types  of  acidosis  is  of  considerable 
interest.  The  behavior  of  acetone  depends  directly  on 
the  carbohydrate  metabolism.  The  ^nation  of  the 
ammonia  is  more  difficult  to  understand.  ^|n  diabetes, 
large  quantities  of  ammon%jire  substituted  for  fixed 
bases  in  the  neutralization  of  acids.  In  the  ordinary 
nephropathies,  the  body  is  unable  to  substitute  any 
ammonia   whatever  for   the  fixed   bases   beyond   the 

X 


**> 


78  THE  PRINCIPLES  OF  ACIDOSIS 

amount,  and  usually  the  minimal  amount,  that  is  nor- 
mally neutralized  in  this  way.  Perhaps  one  of  the  de- 
termining factors  would  be  the  place  of  origin  of  the 
acid  radicals  in  the  body.  In  the  defective  oxidation 
of  diabetes,  the  acid  radicals  and  the  ammonia  might 
conceivably  be  produced  in  the  same  tissues  of  the 
body  or  even  in  the  same  cells,  and  neutralization  could 
readily  take  place.  In  ordinary  nephritis,  however,  the 
acid  radicals  which  the  kidney  fails  to  excrete  might  of 
necessity  take  up  the  fixed  bases,  there  being  no  free 
ammonia  present  in  the  blood  stream  to  effect  the 
neutralization.* 

We  have,  however,  to  deal  not  only  with  the  ques- 
tion of  why  no  additional  ammonia  is  used  in  nephritis ; 
it  remains  to  explain  why  the  amount  in  diabetes  is 
limited  to  40  or  50  per  cent  of  the  total  that  is  excreted. 
The  position  of  the  acidosis  of  cholera  is  unique.  In  its 
etiology,  the  extensive  kidney  lesions  would  apparently 
justify  grouping  it  with  the  other  nephropathies  in 
which  the  function  of  eliminating  acid  is  impaired;  the 
high  ammonia  coefficient,  however,  gives  it  some  re- 
semblance to  the  group  typified  by  defective  oxidation 
of  acids  as  in  diabetes. 

The  observation  of  the  effect  of  alkali  upon  a  high 
ammonia  coefficient  furnishes  the  all-important  distinc- 
tion between  an  increase  in  ammonia  due  to  acidosis 
and  a  similar  increase  due  to  a  primary  disturbance  of 
protein    metabolism.      In    an    uncomplicated    acidosis 

*  It  is  not  in  any  sense  intended  to  imply  that  in  nephritis  the  tissues 
are  unable  to  produce  ammonia  but  rather  that  the  proper  conditions  are 
lacking  for  its  interception  by  acids.  In  other  words  the  appropriate  stimulus 
is  lacking.  Thus  in  the  event  of  the  very  unusual  development  of  diabetes 
with  acidosis  in  a  patient  with  chronic  interstitial  nephritis  one  would  expect 
a  distinct  increase  in  the  urinary  ammonia. 


ETIOLOGY  OF  ACIDOSIS  79 

accompanied  by  a  high  ammonia  coefficient,  the  ad- 
ministration of  bicarbonate,  if  carried  to  the  point  of 
rendering  the  urine  alkaline,  causes  the  ammonia  of  the 
urine  to  fall  promptly  to  normal  or  subnormal  propor- 
tions; the  high  coefficient  represents  merely  a  secondary 
change  in  the  nitrogenous  metabolism  for  compensatory 
purposes.  In  the  primary  disturbances  of  the  protein 
metabolism,  such  as  acute  yellow  atrophy  and  some  of 
the  toxaemias  of  pregnancy,  the  percentage  of  the  total 
nitrogen  of  the  urine  which  is  excreted  as  ammonia  may 
be  both  relatively  and  absolutely  increased.  Further- 
more, this  excretion  of  ammonia  is  unaffected  by  the 
administration  of  bicarbonate.  In  advanced  diabetes 
the  effect  of  bicarbonate  is  sometimes  extremely  inter- 
esting. Unfortunately  there  are  not  very  many  cases 
of  diabetes  in  which  these  data  are  available.  In  a  few 
which  were  studied  in  the  early  investigation  of  acido- 
sis, the  results  proved  to  be  distinctly  instructive.  In 
a  certain  proportion  of  the  cases  the  ammonia  coefficient 
began  to  fall  upon  the  administration  of  bicarbonate. 
However,  with  the  continuation  of  intensive  alkali 
therapy  the  ammonia  output  failed  to  continue  de- 
creasing but  remained  persistently  high.  This  result 
indicates  clearly  that  the  high  ammonia  was  due  in  part 
to  acidosis  and  in  part  to  a  disturbance  of  protein 
metabolism,  perhaps  to  an  impairment  of  liver  function. 
Other  disturbances  of  the  protein  metabolism  also  occur 
in  diabetes.  Occasionally  the  output  of  purin  nitrogen 
in  the  urine  is  considerably  increased.65 

It  is  generally  accepted  in  man  that  the  increase  in 
ammonia  output  in  acidosis  is  accompanied  by  a  cor- 
responding decrease  in  the  output  of  urea,  the  total 
nitrogen  of  the  urine  remaining  constant.     An  impor- 


80  THE  PRINCIPLES  OF  ACIDOSIS 

tant  exception  has  been  discovered  by  McCollum  and 
Hoagland  56  who  find  that  for  certain  omnivora  (swine) 
the  increased  excretion  of  ammonia  in  acidosis  repre- 
sents an  increased  catabolism  of  nitrogen  and  not  an 
interception  of  ammonia  in  the  formation  of  urea. 
There  is  another  difficult  feature  in  the  ammonia  me- 
tabolism which  is  closely  associated  with  acidosis.  In 
some  destructive  diseases  of  the  liver  parenchyma,  the 
output  of  ammonia  increases  markedly,  the  assumption 
being  that  the  urea  forming  function  of  the  liver  has 
been  impaired.  This  view  cannot  be  accepted  as  alto- 
gether satisfactory  until  some  explanation  is  offered  for 
the  failure  of  the  other  tissues  to  take  up  the  function 
of  urea  formation.  It  is  noteworthy  that  in  animals 
with  an  Eck  fistula,  the  ammonia  output  increases 
though  apparently  no  acidosis  develops.  The  entire 
subject  merits  reinvestigation  in  view  of  the  intimate 
relationship  of  hepatic  lesions  to  acidosis  and  to  dis- 
turbances of  the  protein  metabolism. 

One  point  of  very  great  importance  is  the  decision  as 
to  whether  acidosis  is  the  result  or  the  cause  of  nephri- 
tis. From  the  arguments  advanced  in  this  paper,  it 
will  be  seen  that  there  is  strong  evidence  in  favor  of  the 
view  that  the  acidosis  is  a  purely  secondary  phenomenon, 
as  in  diabetes,  and  that  it  is  the  result  of  the  nephritis. 
The  development  of  the  symptoms  of  nephritis  may 
precede,  by  many  months,  all  of  the  signs  of  acidosis; 
advanced  parenchymatous  cases  occur  without  signs  of 
acidosis.  Certainly,  in  chronic  cases,  the  relief  of  aci- 
dosis is  not  followed  by  the  disappearance  of  nephritis. 

In  very  marked  contrast-  to  these  views,  Martin 
Fischer  36  has  advanced  the  idea  that  acidosis  is  the 
cause  of  nephritis.     Fischer  considers  that  there  is  a 


ETIOLOGY  OF  ACIDOSIS  81 

local  production  of  acid  in  the  kidney  substance  in  con- 
trast to  the  view  that  there  is  a  diminished  secretion  and 
elimination  of  acid  by  the  kidney.  The  decision  as  to 
whether  acidosis  is  a  primary  or  secondary  factor  is 
obviously  of  fundamental  importance  from  the  stand- 
point of  etiology  and  therapy.  It  would  be  of  consider- 
able consequence  if  we  could  show  that  some  of  the 
nephropathies  are  caused  by  an  acidosis  and  the  out- 
look for  treatment  would  be  more  hopeful  than  if  we 
find  that  acidosis  is  merely  one  of  several  results  of 
nephritis,  the  cause  itself  being  still  obscure  in  many 
instances.  In  the  fundamental  principle  there  can  be 
no  compromise  between  these  two  views.  The  evidence 
is  overwhelming  that  the  acidosis  is  not  primary  but  is 
purely  secondary,  in  nephritis  as  it  is  in  diabetes,  and 
in  all  other  conditions  in  which  it  has  been  studied. 

There  is  at  present  no  adequate  explanation  for  the 
acidosis  occurring  in  the  so-called  "  food  intoxication  ' 
of  children.  The  excretion  of  "  acetone  bodies  "  is  not 
sufficient  to  indicate  any  serious  disturbance  in  the  proc- 
esses of  oxidation.  The  signs  of  renal  irritation  are 
not  pronounced.  There  is  probably  some  loss  of  alkali 
as  such  from  the  bowel  but  this  would  not  seem  to  be 
sufficient  to  explain  these  cases.  Perhaps  a  combination 
of  these  minor  factors  might  be  sufficient  to  cause  a 
serious  depletion  of  the  fixed  alkali.  It  may  be  that  an 
intensive  study  will  reveal  an  adequate  explanation  of 
these  cases. 

Regarding  the  etiology  of  acidosis,  there  is  one  addi- 
tional possibility  which  possesses  some  theoretical  in- 
terest, namely,  the  effect  of  a  deficit  of  fixed  bases  in  the 
diet,  especially  during  the  period  of  adolescence.  The 
work  of  Osborne,  Mendel  and  Ferry  62  has  shown  the 


82  THE  PRINCIPLES  OF  ACIDOSIS 

importance  of  a  liberal  supply  of  calcium  salts  for  the 
normal  growth  of  young  animals.  It  might  be  of  some 
importance  to  produce  an  impoverishment  of  fixed 
bases  in  the  body  by  limiting  the  amount  of  these  in  the 
food  supply.  Such  a  chronic  acidosis,  during  the  period 
of  growth,  might  conceivably  bear  a  relation  to  some  of 
the  effects  of  malnutrition  seen  in  children. 


XI 

RESUMfi 

Acidosis  may  be  defined  as  a  depletion  of  the  blood 
and  other  tissues  of  the  body  in  fixed  bases.  There  is  no 
accumulation  of  acid  in  the  blood  even  in  fatal  acidoses; 
in  these  cases,  during  the  last  few  days  of  life,  a  definite 
though  very  slight  rise  occurs  in  the  hydrogen  ion  con- 
centration, but  the  blood  still  remains  virtually  neutral 
or  even  faintly  alkaline  ih  a  physicochemical  sense  and 
in  its  reaction  to  indicators.  The  definition  should  not 
be  limited  to  the  blood  nor  to  the  carbonates  alone  but 
it  should  include  the  other  tissues  of  the  body  and  the 
other  fixed  bases  and  substances  which,  like  the  carbon- 
ates, can  give  rise  to  alkali.  Some  of  the  subdivisions 
of  acidosis  which  have  been  proposed  are  essentially 
misleading.  There  is  no  logical  foundation  for  a  distinc- 
tion between  relative  and  absolute  types  or  for  a  clas- 
sification of  cases  into  compensated  and  uncompensated 
groups. 

The  distinction  between  the  normal  and  a  state  of 
acidosis  is  a  quantitative  one  and  not  qualitative  since, 
even  under  physiological  conditions,  the  body  produces 
a  moderate  excess  of  acid  radicals.  These  are  not  per- 
mitted to  appear  as  such  but  are  immediately  disposed 
of  chiefly  by  oxidation  but  in  part  by  excretion  either 
with  or  without  neutralization.  In  acidosis  the  body 
protects  itself,  not  by  the  development  of  new  methods, 
but  by  an  increased  activity  of  its  normal  processes, 
chiefly  through  increased  neutralization  by  ammonia 

83 


84  THE  PRINCIPLES  OF  ACIDOSIS 

and  the  fixed  bases.  This  protective  mechanism  is 
extremely  efficient,  maintaining  a  delicate  adjustment 
of  the  equilibrium  between  acids  and  bases.  In  the 
presence  of  many  factors  which  tend  to  disturb  this 
equilibrium  and  even  with  the  extensive  formation  of 
acid  radicals  in  the  body,  the  reaction  of  the  blood  is 
maintained  with  remarkable  constancy.  The  immediate 
cause  of  death  in  acidosis  is  perhaps  not  the  extremely 
slight  change  in  reaction  per  se  but  rather  the  lack  of 
normal  carbonate  for  carrying  on  the  function  of  in- 
ternal respiration.  In  contrast  to  acidosis,  there  is  no 
adequate  evidence  for  the  establishment  of  the  hypo- 
thetical condition  of  alkalosis  either  in  the  sense  of  an 
increase  in  the  hydroxyl  ion  concentration  of  the  blood 
or  an  increase  in  the  reserve  of  fixed  bases. 

Henderson  has  shown  that  the  precision  with  which 
the  reaction  of  the  blood  is  regulated  constitutes  one  of 
the  great  constants  of  the  body.  In  acidosis  extensive 
changes  are  taking  place  in  the  body  to  maintain  this 
regulation.  Since  the  reaction  of  the  blood  remains  un- 
affected other  methods  must  be  adopted  to  detect  these 
changes.  The  determination  of  the  tolerance  to  sodium 
bicarbonate  (i.  e.,  the  amount  of  bicarbonate  required 
to  render  the  urine  alkaline)  has  been  developed  as  a 
test  for  acidosis.  It  constitutes  the  most  delicate  test 
which  we  have,  since  changes  occur  in  the  bicarbonate 
tolerance  before  the  carbonates  of  the  blood  show  any 
definite  diminution.  Furthermore,  it  is  of  general  ap- 
plication in  all  types  of  acidosis  which  have  been  de- 
scribed and  it  is  pathognomonic.  By  the  aid  of  this 
test  in  conjunction  with  observations  on  the  reaction  of 
the  blood  to  phenolphthalein,  it  was  proven  that  a 
moderate  degree  of  acidosis  develops  comparatively 


RESUMfi  85 

early  in  some  of  the  chronic  nephritides.  Conclusive 
proof  was  also  furnished  that  the  high  tolerance  to  bi- 
carbonate found  in  advanced  nephritis  is  due  essentially 
to  an  acidosis.  This  conclusion  was  confirmed  by  dem- 
onstrating  a  marked  lowering  of  the  carbon  dioxide  con- 
tent of  the  blood  in  uraemia.  Three  cases  of  diabetes 
were  described  in  which  an  acidosis  occurred  that  was 
not  due  to  the  ordinary  "  acetone  bodies." 

The  establishment  of  the  existence  of  acidosis  in 
several  of  the  nephropathies  broadens  our  views  con- 
siderably in  regard  to  the  essential  features  of  acidosis. 
In  certain  types  of  uraemia  and  acute  nephritis  we  have 
an  acidosis  fully  as  severe  as  any  that  occurs  in  diabetes. 
Yet  it  is  not  dependent  in  any  sense  upon  a  disturbance 
of  carbohydrate  metabolism,  the  amount  of  acetone  in 
the  urine  remains  within  normal  limits  and  there  is  no 
excretion  of  the  other  '  acetone  bodies."  The  am- 
monia excretion  both  as  regards  the  relative  and  ab- 
solute amounts  is  not  increased.  In  any  acidosis  there 
are  several  fundamental  features  which  develop  as  a 
direct  result  of  the  depletion  of  the  body  in  fixed  bases. 
The  tolerance  to  bicarbonate  rises  and  the  carbon  diox- 
ide content  of  the  blood  and  alveolar  air  as  well  as  the 
titratable  alkalinity  of  the  blood  diminishes.  In  fatal 
cases  there  is  a  slight  decrease  in  the  actual  alkalinity 
of  the  blood  just  before  death.  As  incidental  features 
in  the  course  of  acidosis  we  may  have  an  increase  in  the 
excretion  of  the  "  acetone  bodies  "  and  of  ammonia. 

This  variation  in  the  ammonia  is  surprising.  It 
has  long  been  known  that  the  herbivora  can  supply 
ammonia  much  less  readily  than  the  carnivora  in  the 
neutralization  of  acids.57  However,  it  had  not  been 
suspected  that  wide  variation  occurs  in  a  given  species 


86  THE  PRINCIPLES  OF  ACIDOSIS 

according  to  the  mode  of  origin  of  the  acidosis.  The 
early  study  of  diabetes  led  to  the  natural  conclusion 
that  in  man  ammonia  was  always  readily  available  in 
acidosis.  In  the  event  that  nephritis  had  been  studied 
before  diabetes,  the  reverse  impression  would  have  held. 
In  diabetes,  although  a  large  proportion  (50  per  cent)  of 
the  available  ammonia  is  often  utilized,  it  still  remains 
to  explain  why  all  of  the  ammonia  cannot  be  employed. 
In  nephritis  the  ammonia  excretion  often  reaches  only 
the  lower  limits  of  normal,  the  more  valuable  fixed 
bases  being  utilized  very  extensively.  It  might  seem 
that  in  the  acidoses  due  to  defective  oxidation,  the  am- 
monia output  is  high  whereas  it  is  normal  or  even  sub- 
normal in  those  caused  by  defective  renal  function.  An 
apparent  exception  to  this  proposition  is  found  in  the 
disease,  Asiatic  cholera,  which  occupies  a  unique  posi- 
tion; the  nephritis  is  extreme,  the  acetone  output  is 
normal  but  the  ammonia  is  high.  Some  information 
might  be  obtained  in  explanation  of  these  difficulties  if 
acidosis  could  be  produced  experimentally  without  in- 
creasing the  excretion  of  ammonia. 

Three  conditions  are  known  in  which  severe  acidosis 
occurs,  namely,  diabetes,  some  of  the  nephropathies 
and  the  so-called  "  food  intoxication  "  of  children.  The 
clinical  symptoms  of  air  hunger  and  coma  develop  and 
the  acidosis  frequently  becomes  the  immediate  cause  of 
death.  Occasionally  pronounced  symptoms  of  acidosis 
develop  in  patients  with  advanced  lesions  of  the  liver 
but  these  cases  have  not  been  adequately  studied.  Mod- 
erate symptoms  of  acidosis  not  infrequently  develop 
in  acute  rheumatic  fever  and  in  advanced  anaemias. 
Except  for  the  fact  that  the  compensatory  processes 
operate  effectively,  it  seems  not  unlikely  that  the  dis- 


RfiSUMfi  87 

turbances  arising  from  acidosis  would  be  much  more 
common.  The  occurrence  of  a  definite  degree  of  acido- 
sis in  uncomplicated  cardiac  cases  has  not  been  es- 
tablished. The  tests  for  acidosis  may  be  very  helpful 
in  the  rapid  differentiation  of  various  comas  and  in  the 
study  of  cardiorenal  and  cerebral  lesions. 

In  the  treatment  of  acidosis  with  alkalies  it  should  be 
remembered  that  the  relief  of  symptoms  is  due  not  to 
the  neutralization  of  acid  but  to  the  persistence  of  the 
injected  carbonates  in  the  body  and  to  their  function 
in  carrying  carbon  dioxide  from  the  tissues  to  the  lungs. 
Some  of  the  supposedly  toxic  symptoms  of  uraemia  are 
due,  not  to  the  presence  of  a  toxin,  but  to  the  absence  of 
a  normal  constitutent  of  the  body,  namely,  the  carbon- 
ates. The  fixed  bases  especially  the  carbonates  are 
essential  to  life.  When  a  depletion  of  carbonates  occurs, 
the  carbon  dioxide  accumulates  in  the  tissues,  the 
oxygen  brought  to  the  tissues  by  the  arterial  blood  can- 
not be  utilized  but  is  carried  away  by  the  venous  blood. 
The  effect  is  equivalent  to  depriving  the  individual  of 
oxygen;  such  patients  suffer  from  symptoms  of  suffo- 
cation and  frequently  call  for  "  air."  From  the  study 
of  cases  of  acidosis  it  is  possible  to  determine  in  a  gen- 
eral way  the  effect  of  varying  degrees  of  depletion  in  the 
supply  of  fixed  bases  in  the  body.  A  deficit  of  20  or  30 
grams  can  be  detected  by  appropriate  laboratory  meth- 
ods but  certainly  does  not  produce  any  clinical  symp- 
toms. A  deficit  of  40  to  50  grams  produces  changes 
which  can  readily  be  detected  by  a  variety  of  laboratory 
methods  but  still  does  not  spontaneously  give  rise  to 
clinical  symptoms  other  than  dyspnoea  on  exertion. 
With  an  increase  of  this  deficit  to  75  or  100  grams  dysp- 
noea may  develop  and  may  persist  even  when  patients 


88  THE  PRINCIPLES  OF  ACIDOSIS 

are  at  rest  in  bed.  More  rarely  there  may  also  be  slight 
mental  confusion.  Several  patients  in  whom  the  deficit 
amounted  to  approximately  150  grams  of  bicarbonate 
were  in  partial  coma  and  showed  varying  but  definite 
evidences  of  air  hunger.  The  maximum  deficits  which 
have  been  reported  either  in  diabetes  or  nephritis  are 
about  200  grams.  Such  patients  are  always  in  coma 
and  it  would  seem  that  this  quantity  represents  ap- 
proximately the  critical  limit  of  depletion  in  fixed  bases. 

The  behavior  of  the  fixed  bases  in  acidosis  apparently 
conforms  to  a  somewhat  general  pathological  law  that 
the  composition  of  the  blood  is  maintained  in  a  rela- 
tively constant  condition  at  the  expense  of  the  other 
tissues  of  the  body.  Thus  if  the  organism  suffers  a 
depletion  in  water  or  in  carbohydrates,  the  other  tissues 
of  the  body  are  drawn  upon,  even  to  the  point  of  exhaus- 
tion, to  maintain  a  fairly  normal  composition  of  the 
blood  in  these  substances.  The  physicochemical  reac- 
tion of  the  blood  is  protected  and  maintained  at  a  con- 
stant level  with  great  care. 

The  requirements  are  comparatively  simple  for  the 
appropriate  use  of  alkalies  in  acidosis.  For  the  fully 
developed  cases  in  which  coma  is  pending  it  is  necessary 
to  use  large  injections  of  bicarbonate  intravenously 
rather  than  the  normal  carbonate.  Its  administration 
must  be  controlled  in  a  general  way  by  the  examination 
of  the  blood  serum  for  titratable  alkalinity  or  carbon 
dioxide  or  by  the  carbon  dioxide  content  of  the  alveolar 
air.  The  exact  point  at  which  the  administration  of 
alkali  should  cease  must  be  determined  more  exactly  by 
carefully  following  the  reaction  of  the  urine.  Fortu- 
nately the  reaction  of  the  urine  affords  an  entirely  re- 
liable guide  even  in  patients  with  advanced  lesions  of 


RESUME  89 

the  kidney.  This  fact  is  of  considerable  clinical  impor- 
tance. In  mild  or  doubtful  cases  of  acidosis  it  is  entirely 
permissible  to  give  sodium  bicarbonate  in  5  gram  quan- 
tities at  two  hour  intervals  until  the  urine  becomes 
alkaline. 

In  acute  and  self-limited  conditions  accompanied  by 
severe  acidosis,  treatment  with  alkalies  is  sometimes 
very  satisfactory.  The  best  and  most  uniform  results 
are  obtained  in  Asiatic  cholera.  In  chronic  conditions 
the  effect  of  treatment  is  so  discouraging  that  the  use 
of  alkalies  in  diabetic  acidosis  is  often  neglected  and 
the  possibilities  of  this  procedure  are  by  no  means  fully 
realized.  Some  observers  even  go  so  far  as  to  advise 
against  the  use  of  alkalies.  While  the  ideal  object  in 
diabetes  is  to  prevent  the  development  of  acidosis  yet 
when  this  condition  does  appear  it  should  be  promptly 
relieved  with  bicarbonate.  This  treatment  with  alkalies 
is  just  as  essential  as  the  relief  of  any  other  form  of 
starvation.  In  chronic  nephritis,  acidosis  develops  com- 
paratively early;  it  frequently  leads  to  serious  discom- 
fort and  may  prove  to  be  the  immediate  cause  of  death. 
The  early  relief  of  this  acidosis  might  possibly  have  a 
beneficial  effect  on  the  course  of  the  nephritis  notwith- 
standing that  a  low  grade  of  chronic  acidosis  is  pre- 
sumably without  effect  on  metabolism.  In  passing,  it 
might  be  mentioned  that  a  meat  diet,  so  often  detri- 
mental to  nephritics,  is  comparatively  rich  in  the  acid 
end-products  of  catabolism. 

In  chronic  acidosis  it  is  therefore  a  long  and  difficult 
problem  to  determine  the  clinical  effect  of  treatment; 
on  the  other  hand  the  changes  produced  in  the  labora- 
tory findings  by  the  injection  of  alkali  are  prompt  and 
easily  recognized.    The  carbon  dioxide  content  of  the 


9a  THE  PRINCIPLES  OF  ACIDOSIS 

alveolar  air  and  the  blood  rises  rapidly  to  normal.  The 
titratable  alkalinity  of  the  blood  increases  and  the  tol- 
erance to  bicarbonate  of  course  decreases.  In  diabetes 
the  ammonia  output  falls  but  it  is  extremely  important 
to  determine  whether  the  ammonia  excretion  can  be 
reduced  to  normal.  A  polyuria  often  ensues  accom- 
panied by  an  increased  excretion  of  the  "  acetone 
bodies  "  owing  to  a  flushing  out  of  the  tissues. 

The  etiology  of  the  known  acidoses  resolves  itself  into 
two  fundamental  types  namely,  defective  oxidation  of 
organic  acids  as  typified  by  diabetes  and  defective  elim- 
ination more  especially  of  the  mineral  acids  as  found  in 
the  ordinary  nephropathies.  There  are  certain  things 
which  suggest  that  perhaps  the  nephritis  of  cholera 
represents  a  combination  of  these  two  types. 

One  of  the  essential  functions  of  the  kidney  is  the 
rather  remarkable  separation  of  a  sharply  acid  urine 
from  a  slightly  alkaline  blood  plasma.  Impairment  of 
this  function  is  apparently  one  of  the  principal  factors 
in  the  development  of  acidosis  in  nephritis.  Notwith- 
standing the  progressive  development  of  the  renal 
lesions,  the  kidney  retains,  in  a  very  considerable  de- 
gree, its  remarkable  ability  of  separating  and  excreting 
acids  and  acid  salts  from  a  slightly  alkaline  plasma. 
This  is  one  of  the  last  functions  of  the  kidney  to  be  lost, 
persisting  as  long  as  fluid  is  excreted. 

No  adequate  explanation  has  as  yet  been  offered  for 
the  extreme  acidosis  occurring  in  children. 

Before  dismissing  the  subject  of  acidosis,  it  might  be 
well  to  mention  again  the  points  arising  in  this  discus- 
sion on  which  the  information  at  present  is  incomplete. 
The  extent  to  which  acidosis  occurs  in  diseases  involving 
the  liver  cannot  be  determined  until  laboratory  data  are 


RfiSUMfi  91 

available.  There  is  urgent  need  for  some  alleviating 
measures  in  chronic  nephritis  and  the  early  treatment 
of  acidosis  is  a  logical  procedure  and  offers  possible, 
even  though  minor  assistance.  Another  feature  of 
treatment  which  merits  attention  is  the  replacement  of 
calcium  and  magnesium  as  well  as  the  carbonates.  The 
explanation  of  the  ammonia  metabolism  in  nephritis  is 
an  involved  and  interesting  problem.  Its  behavior 
cannot  be  completely  understood  until  further  investi- 
gations are  made  in  Asiatic  cholera.  It  is  not  incon- 
ceivable that  an  acidosis  of  a  special  type  might  result 
from  the  withholding  of  the  normal  fixed  bases  of  the 
food.  During  the  adolescent  period  such  a  deprivation 
might  result  in  the  production  of  unusual  features 
which  would  not  be  possible  in  adult  life. 


XII 
APPENDIX 


APPENDIX 

TECHNIQUE  OF  METHODS 

In  the  following  pages  only  those  methods  will  be  described 
which  have  been  developed  recently  and  which  are  of  clinical 
importance.  The  older  methods  for  the  study  of  diabetic 
acidosis  are  well  known.  The  determination  of  the  ammonia 
coefficient  is  now  extremely  simple.  No  fundamental  changes 
have  been  introduced  in  Kheldahl's  method  for  total  nitrogen 
but  the  introduction  of  micro-methods  by  Folin  has  reduced 
the  required  laboratory  facilities  to  a  minimum.  The  de- 
termination of  ammonia  was  formerly  greatly  hindered  by 
the  ease  with  which  the  urea  of  the  urine  changed  to  am- 
monia under  the  influence  of  heat  and  alkalies.  This  difficulty 
has  been  entirely  obviated  by  Folin's  methods  of  removing 
the  ammonia  from  the  urine  by  aeration  in  the  cold.  The 
removal  is  quantitative  and  the  ammonia  is  absorbed  in 
standard  acid  and  measured  by  titration.58  The  acetone  and 
/3-oxybutyric  acid  content  of  the  urine  can  be  very  readily 
determined  by  Shaffer's  method.59  The  acetone  is  first  dis- 
tilled off,  the  remaining  /5-oxybutyric  acid  being  oxidized 
with  potassium  bichromate  to  acetone  and  carbon  dioxide. 
The  quantity  of  acetone  is  determined  volu metrically  with 
standard  iodine.  Marriott  has  also  developed  a  method  for 
the  determination  of  acetone  and  /3-oxybutyric  acid  in  the 
blood  and  tissues.60 

Those  methods  which  serve  for  the  detection  of  any  aci- 
dosis regardless  of  its  mode  of  origin  are  of  especial  interest. 
Some  of  these  will  be  described  in  detail. 

Carbon  Dioxide  Content  of  the  Alveolar  Air.  This  determi- 
nation resolves  itself  into  two  phases,  namely,  (1)  the  collec- 
tion of  the  specimen,  and  (2)  its  analysis.    There  is  a  choice 

95 


96  THE  PRINCIPLES  OF  ACIDOSIS 

of  two  types  of  methods  for  the  collection  of  samples  of  alveo- 
lar air.  In  one  type,  after  a  normal  expiration,  the  residue 
of  alveolar  air  is  expelled  by  a  forcible  deep  expiration  and 
caught  in  a  suitable  tube;  in  the  other,  the  subject  is  required 
to  rebreathe  a  small  volume  of  air  in  an  ordinary  rubber  bag 
for  half  a  minute.  Haldane  devised  the  method  for  collecting 
the  alveolar  air  by  a  forcible  expiration.  There  are  several 
modifications  of  this  type  all  of  which  require  more  or  less 
skill  on  the  part  of  the  subject.  Boothby  and  Peabody  6l 
have  improved  the  method  by  the  introduction  of  certain 
automatic  features  in  the  apparatus  for  collecting  and  trap- 
ing  the  expired  air;  even  with  this  advancement  these 
authors  do  not  recommend  this  type  of  method  except  for 
special  investigations  on  trained  subjects  or  for  patients 
who  can  cooperate  readily.  Under  such  conditions  the  Fride- 
ricia  62  method  is  perhaps  the  simplest  and  it  is  sufficiently 
accurate  for  clinical  purposes.  The  alveolar  air  is  caught  by 
forcible  expiration  in  a  glass  tube,  the  carbon  dioxide  is  ab- 
sorbed by  caustic  soda  and  the  decrease  in  volume  is  measured 
on  a  scale  reading  in  percentages  by  volume.  A  very  careful 
and  accessible  description  of  the  method  is  given  by  Poulton62a 
in  which  the  main  features  are  as  follows.  A  convenient  form 
of  the  apparatus  is  illustrated  in  Figure  1.  M  is  a  mouth- 
piece. A  is  an  ordinary  two-way  and  B  a  three-way  stopcock 
of  rather  wide  bore  (10  millimeters).  Three  positions  of  the 
stopcock  B  are  required  during  the  procedure  in  the  following 
order,  namely : 

Position     I.   In  which  X  and  Y  communicate,  the  outlet  C 
being  cut  off. 
"  II.   Y  and  C  communicate,  X  being  cut  off. 

"        III.   X  and  C  communicate,  Y  being  cut  off. 

The  total  volume  of  X  between  A  and  B  must  be  exactly 
100  c.c.  and  the  scale  in  the  narrow  stem  of  X  is  graduated 
in  cubic  centimeters  or,  to  obviate  the  difficulty  of  construct- 
ing X  to  contain  exactly  100  c.c,  an  approximate  size  may  be 


A 

u 

Jc 

Fig.  1.  Feidericia  Apparatus. 


APPENDIX.    TECHNIQUE  OF  METHODS      97 

used;  the  volume  is  then  determined  exactly  and  the  scale 
is  graduated  in  percentages  of  this  volume  up  to  eight  per 
cent.  The  subject  must  breathe  quietly  into  the  apparatus 
with  the  tap  A  open  and  B  in  Postition  I.  At  the  end  of  a 
normal  inspiration  he  blows  hard  and  quickly  through  the  ap- 
paratus and  the  operator  closes  tap  A  leaving  B  unchanged. 
Inasmuch  as  the  total  volume  of  the  forced  expiration  is 
about  two  liters  this  procedure  displaces  all  the  air  in  the  ap- 
paratus and  leaves  it  filled  with  alveolar  air.  The  apparatus 
is  placed  in  a  water-bath  at  room  temperature.  On  cooling, 
alveolar  air  in  the  bottom  of  Y  is  drawn  into  X  but  there  is 
no  danger  that  the  atmospheric  air  drawn  into  the  top  of  Y 
can  reach  X.  After  five  minutes  the  stopcock  B  is  turned 
into  position  II  connecting  Y  and  the  outlet,  but  closing  X. 
By  means  of  suction  at  the  top  of  Y  (a  rubber  bulb)  20  per 
cent  sodium  hydroxide  (about  2  or  3  c.c.)  is  sucked  into  Y. 
With  X  and  Y  in  communication  (Position  I)  the  soda  is 
forced  under  slight  pressure  into  X  compressing  the  alveolar 
air  to  admit  the  addition  of  the  soda  keeping  the  stopcock 
A  closed.  During  the  manipulation  the  arm  Y  is  depressed 
slightly  and  X  is  elevated  to  prevent  any  alveolar  air  escaping 
through  B.  The  next  step  consists  in  closing  X,  turning  the 
stopcock  to  Position  II  and  the  caustic  soda  remaining  in  Y 
is  allowed  to  run  out.  The  apparatus  is  inverted  with  gentle 
shaking  for  a  half  minute  to  effect  the  absorption  of  the  car- 
bon dioxide;  it  is  then  returned  to  the  water-bath,  and  the 
stopcock  B  turned  with  the  tap  C  under  water  so  that  X 
communicates  through  C  with  the  water  (Position  III) .  After 
five  minutes  the  instrument  is  raised  till  the  water  stands 
at  the  same  level  in  X  and  in  the  water-bath.  This  opera- 
tion brings  the  gas  in  X  to  the  same  conditions  of  tempera- 
ture and  pressure  as  before  absorption.  Consequently  the 
reading  at  the  meniscus  of  the  fluid  in  the  stem  of  X  represents 
without  any  correction  the  percentage  of  carbon  dioxide  in 
the  sample  since  no  allowance  is  made  for  the  water  vapor 
taken  up  by  the  alkali;  this  correction  for  the  absorbed  water 


98  THE  PRINCIPLES  OF  ACIDOSIS 

vapor  would  fall  within  the  limits  of  error  of  the  method. 
If  it  is  desired  to  transpose  these  figures  to  millimeters  of 
mercury  for  the  corresponding  conditions  of  temperature 
pressure  and  water  vapor  one  need  only  multiply  the  baro- 
meter reading  by  the  percentage.  Thus  at  sea  level  a  normal 
reading  of  5.5  per  cent  would  correspond  to  about  42  milli- 
meters of  mercury.  In  cleansing  the  apparatus,  it  is  well  to 
use  a  little  dilute  acid  to  insure  freedom  from  any  trace  of 
alkali. 

In  the  process  of  collecting  the  sample  there  are  two  pre- 
cautions which  the  patient  must  be  taught  to  observe.  In 
the  first  place  there  is  an  involuntary  tendency  to  take  a  deep 
inspiration  before  the  forced  expiration.  This  dilutes  the 
sample  and  gives  readings  that  are  too  low,  sometimes  by 
one-half  per  cent.  If  this  error  of  deep  breathing  is  over- 
corrected  and  the  breath  is  held  even  for  a  few  moments  (5 
seconds)  before  the  expiration,  then  the  results  will  be  too 
high  (one-half  to  one  per  cent). 

While  the  Fridericia  method  is  very  simple  and  sufficiently 
accurate  for  trained  subjects  it  is  unsuitable  for  a  compara- 
tively large  group  of  subjects  such  as  patients  in  more  or  less 
complete  coma  and  in  the  case  of  infants.  For  routine  clini- 
cal purposes,  Plesch's  procedure  of  rebreathing  air  has  be- 
come generally  adopted.  The  most  satisfactory  form  of  this 
method  is  the  Plesch-Higgins  modification.  The  exact  de- 
tails as  employed  by  Boothby  and  Peabody  61  are  as  follows: 
A  soft  rubber  bag  of  one  and  one-half  to  two  liters  capacity 
is  provided  with  a  mouthpiece.  Between  the  mouthpiece  and 
the  bag  it  is  desirable  to  introduce  a  three-way  stopcock  so 
that  the  subject  can  breathe  through  the  mouthpiece  either 
to  the  outer  air  or  into  the  bag.  This  stopcock  should  have 
a  large  lumen  (one-half  inch)  to  permit  free  and  natural 
breathing.  A  small  tube  with  an  ordinary  stopcock  should 
also  be  added  to  the  apparatus  for  the  purpose  of  withdrawing 
samples  of  air  for  analysis.  In  trained  individuals  who  can 
cooperate  freely  it  is  possible  to  dispense  with  the  three-way 


APPENDIX.  TECHNIQUE  OF  METHODS      99 

stopcock.     Even  in  comatose  patients  and  in  children  some 
workers  use  a  simple  bag  without  the  stopcock,  but  this 
routine  tends  to  diminish  one's  confidence  in  the  samples 
which  are  obtained.    By  displacement  with  water  the  bag  is 
partially  filled  with  air  using  approximately  1000  cubic  centi- 
meters.   Except  for  purposes  of  special  study  it  is  sufficient 
to  introduce  very  roughly  about  this  amount  with  a  rubber 
bulb.    Next  the  three-way  stopcock  is  opened  to  the  outer 
air  and  the  subject  with  the  nostrils  compressed  breathes 
quietly    through    the    mouthpiece   for   several   respirations. 
Then  at  the  end  of  a  normal  expiration  the  stopcock  is  turned 
and  the  subject  breathes  into  the  bag  for  20  to  30  seconds 
only,  preferably  for  25  seconds  taking  5  moderately  deep 
breaths.    If  the  depth  and  rate  of  breathing  cannot  be  con- 
trolled, a  correction  may  be  made  by  slightly  altering  the 
time  period  and  the  final  result  is  not  greatly  affected.    Modi- 
fications of  this  technique  are  often  necessary  for  patients  in 
more  or  less  complete  coma  and  for  children.    For  such  cases 
the  mouthpiece  must  be  supplemented  by  a  mask  made  of  a 
thin  sheet  of  rubber.    Suitable  technique  for  infants  has  been 
worked  out  by  Howland  and  Marriott.63    A  smaller  bag,  one 
of  500  c.c.  capacity,  is  partially  filled  with  air  from  an  aspira- 
tor bulb  using  250  c.c.  to  400  c.c.  according  to  the  age  of  the 
subject.    The  initial  amount  should  be  such  that  at  the  end  of 
inspiration,  the  bag  is  from  one-half  to  two-thirds  empty. 
The  child  is  allowed  to  breathe  into  the  bag  for  one-half 
minute.     Vigorous  crying  just  before  collection  lowers  the 
tension  while  crying  during  the  collection  is  an  advantage  and 
raises  the  tension  only  an  insignificant  amount. 

After  the  collection  of  the  sample  the  estimation  of  the 
carbon  dioxide  may  be  made  by  any  of  the  standard  methods 
for  gas  analysis.  The  Haldane  method  of  gas  analysis  is  very 
satisfactory  for  those  who  wish  to  go  into  the  subject  rather 
thoroughly.64  For  clinical  purposes  the  Fridericia  method  is 
sufficient.  The  specimen  of  gas  should  be  thoroughly  mixed 
in  the  rubber  bag  and  then  transferred  to  the  sample  bulb 


100  THE  PRINCIPLES  OF  ACIDOSIS 

(X  in  Fig.  1)  of  the  Fridericia  apparatus.  This  may  be  readily 
done  by  washing  out  the  atmospheric  air  with  a  few  hundred 
cubic  centimeters  of  the  sample  of  alveolar  air.  If  preferred 
the  bulb  may  be  filled  by  displacement  of  water  or  mercury. 
The  absorption  of  the  carbon  dioxide  with  soda  is  then  carried 
out  as  previously  described. 

Marriott 17  has  recently  introduced  a  simple  method  of 
analysis  in  which  a  solution  of  alkali  is  saturated  with  the 
mixture  of  gases  to  be  analyzed.  The  reaction  of  the  alkaline 
solution  changes  in  proportion  to  the  amount  of  carbon  diox- 
ide contained  in  the  alveolar  air,  the  greater  the  amount  of 
carbon  dioxide  (carbonic  acid),  the  less  alkaline  the  solution 
becomes.  Solutions  of  sodium  hydroxide  or  sodium  bicarbon- 
ate will  readily  take  up  carbon  dioxide  according  to  the  fol- 
lowing equations : 

2  NaOH  +  C02  =  Na2C03  +  H20 

and 
Na2C03  +  C02  +  H20  =  2  NaHC03 

The  striking  feature  of  these  reactions  is  that  they  do  not  go 
to  completion.  A  high  concentration  of  carbon  dioxide  will 
result  in  the  formation  of  large  quantities  of  bicarbonate  and 
smaller  proportions  of  carbon  dioxide  in  proportionately 
smaller  amounts.  This  difference  cannot  be  overcome  by 
employing  larger  amounts  of  the  weaker  mixture  of  carbon 
dioxide  and  prolonging  the  length  of  time  which  it  is  bubbled 
through  the  alkali.  The  alkaline  solution  soon  comes  into 
equilibrium  with  a  given  mixture  of  carbon  dioxide  and  air 
and  is  then  unable  to  absorb  any  additional  carbon  dioxide 
from  this  mixture;  the  carbon  dioxide  escapes  from  solution 
notwithstanding  that  there  is  considerable  sodium  hydroxide 
and  sodium  carbonate  which  is  not  converted  to  bicarbonate. 
If  to  such  a  solution  one  adds  some  sodium  bicarbonate  it 
could  not  remain  as  such  but  would  be  in  part  converted  to 
the  carbonate  and  hydroxide.  The  change  involved  in  main- 
taining this  equilibrium  after  the  addition  of  the  bicarbonate 


APPENDIX.   TECHNIQUE  OF  METHODS     101 

may,  under  appropriate  conditions  of  concentration,  be  rep- 
resented by  the  following  reaction, 

2  NaHC03  =  Na2C03  +  H20  +  C02, 

the  carbon  dioxide  escaping  from  the  solution.  It  is  indeed 
surprising  to  see  the  solution  become  more  alkaline  as  the 
carbon  dioxide  is  passed  through  it. 

The  application  of  these  principles  is  very  simple.  The 
sample  of  alveolar  air  is  bubbled  through  a  few  cubic  centi- 
meters of  a  standard  alkali  (carbonate,  bicarbonate  or 
hydroxide)  and  the  resulting  reaction  is  proportional  to  the 
tension  of  carbon  dioxide  in  the  specimen  of  alveolar  air. 
The  reaction  may  be  conveniently  determined  colorimetri- 
cally  with  phenolsulphonephthalein  as  indicator.  This  re- 
agent varies  in  color  according  to  the  degree  of  alkalinity  of 
the  solution;  the  more  strongly  alkaline  solutions  being  red, 
the  faintly  alkaline  ones  orange  and  slightly  acid  solutions  are 
yellow.  A  scale  of  color  standards  is  prepared  from  1/15 
molecular  stock  solutions  of  acid  potassium  phosphate 
(KH2P04)  and  the  dibasic  sodium  phosphate  (Na2HP04). 
Of  the  recrystallized  acid  potassium  phosphate  9.078  grams 
are  dissolved  in  distilled  water,  200  c.c.  of  0.01  per  cent  phen- 
olsulphonephthalein are  added  and  the  total  volume  made 
to  one  liter.  For  the  alkaline  sodium  phosphate  the  recrystal- 
lized salt  (Na2HP04.12  H20)  is  exposed  to  the  air  for  two 
weeks  thereby  losing  10  molecules  of  water  of  crystallization. 
Of  the  salt  containing  two  molecules  of  water,  11.876  grams 
are  dissolved  in  water,  200  c.c.  of  0.01  per  cent  phenolsul- 
phonephthalein are  added  and  the  total  volume  made  up  to 
one  liter  as  for  the  acid  salt.  The  following  table  gives  the 
gradations  of  color  standards  recommended  by  Marriott  and 
the  corresponding  equivalent  of  carbon  dioxide  in  terms  of 
its  tension  in  millimeters  of  mercury. 


102 


THE  PRINCIPLES  OF  ACIDOSIS 


Serial  number 

1 

2 

3 

4 

5 

6 

7 

8 

Acid    potassium    phos- 

17.8 

25.2 

31.0 

35.7 

40.5 

45.0 

47.0 

50.2 

Alkaline   sodium   phos- 

82.2 

74.8 

69.0 

64.3 

59.5 

55.0 

53.0 

49.8 

Tension  of  CO2  (mm.  of 
mercury)  corresponding 
to  this  reaction 

10 

15 

20 

25 

30 

35 

40 

45 

These  standards  must  be  kept  in  closed  tubes  and  protected 

(N) 
from  the  light.  The  standard  alkali  :  ,  is  made  by  dissolv- 
ing 0.53  gram  of  anhydrous  sodium  carbonate  in  water,  adding 
the  usual  200  c.c.  of  0.01  per  cent  phenolsulphonephthalein 
and  making  the  total  volume  up  to  one  liter.  It  is  desirable 
to  pass  the  breath  from  the  lungs  through  this  to  the  point 
of  saturation  in  order  that  the  carbonate  content  shall  cor- 
respond approximately  to  that  of  normal  alveolar  air;  then 
if  it  is  too  high  or  too  low,  it  will  adjust  itself  to  the  reaction 
corresponding  to  the  alveolar  specimen  with  which  it  is 
aerated.  For  the  analysis,  a  few  cubic  centimeters  of  the 
standard  alkali  are  poured  into  a  tube  of  the  same  dimen- 
sions as  those  containing  the  color  standards.  The  operator 
adjusts  this  approximately  with  his  own  breath.  Then  about 
100  c.c.  of  the  alveolar  air  under  examination  are  blown 
rather  rapidly  (in  30  seconds)  through  the  solution  from  a 
capillary  pipette.  When  no  further  change  in  color  occurs, 
it  follows  that  the  solution  is  saturated;  its  color  is  then 
compared  with  the  standards.  Marriott  recommends  that 
this  should  be  done  against  a  ground  glass  background  using 
an  apparatus  of  the  type  of  the  Sahli-haemoglobinometer  but 


APPENDIX.  TECHNIQUE  OF  METHODS     103 

holding  not  less  than  3  tubes.  After  the  comparison  has 
been  made  the  same  solution  may  be  used  repeatedly  for  new 
determinations. 

Experience  in  various  laboratories  has  shown  that  this 
method  is  satisfactory  for  clinical  purposes  in  the  hands  of 
careful  workers  provided  one  is  occasionally  in  a  position  to 
check  the  results  with  more  elaborate  equipment.  It  is 
highly  desirable  that  a  person  employing  this  method  should 
control  his  technique  from  time  to  time  by  some  of  the  other 
methods  for  carbon  dioxide  analysis. 

Examination  of  the  Blood 

In  the  examination  of  the  blood  the  principal  features  con- 
cerning acidosis  are  the  titratable  alkalinity,  the  carbon  diox- 
ide content  and  the  physicochemical  reaction. 

Reaction  of  Serum  to  Phenolphthalein  after  Removal  of  the 
Proteins.  Numerous  methods  have  been  devised  for  measur- 
ing the  titratable  alkalinity  of  the  blood  against  dilute 
standard  acid  using  preferably  methyl  orange  as  indicator. 
The  end  point  is  extremely  vague  and  the  differences  between 
the  normal  and  pathological  are  at  best  only  suggestive  and 
not  definite.  One  serious  interfering  factor  is  the  protein  of 
the  serum. 

To  obviate  some  of  these  difficulties  the  following  depar- 
ture was  made  from  the  usual  titration  methods,25  (1)  an 
indicator  was  selected  to  which  unheated  blood  serum  ordi- 
narily reacts  acid,  in  contrast  to  litmus  or  the  diazo  group 
to  which  serum  reacts  distinctly  alkaline,  (2)  the  interfering 
protein  was  removed,  and  (3)  a  solvent  was  chosen  which 
would  decrease  the  ionization  of  the  carbonates  so  that  they 
would  give  rise  to  less  alkali  than  when  dissolved  in  water. 
These  changes  are  made  with  the  object  of  reducing  the  nor- 
mal titratable  alkalinity  to  a  minimum.  In  acidosis  this 
alkalinity  disappears  altogether  and  one  has  at  once  a  definite 
qualitative  test  for  its  detection.  The  removal  of  protein 
and  the  substitution  of  another  solvent  for  water  was  ac- 


104  THE  PRINCIPLES  OF  ACIDOSIS 

complished  in  one  step  by  precipitation  with  alcohol.  The 
behavior  of  indicators  in  alcoholic  solution  is  very  interesting. 
If  a  little  alkaline  phenolphthalein  dissolved  in  water  and 
alcohol  is  poured  into  a  beaker  of  pure  alcohol,  the  color  is  at 
once  discharged.  This  is  due  not  to  any  traces  of  acid  in  the 
alcohol  but  to  a  decrease  in  the  ionization  of  the  hydroxide  in 
alcohol.  Consequently,  in  order  to  produce  a  red  color  with 
phenolphthalein,  a  larger  amount  of  alkali  must  be  used  in 
alcoholic  than  in  aqueous  solution. 

In  the  selection  of  an  absolute  ethyl  alcohol  for  alkalinity 
work,  it  must  be  noted  that  different  specimens  vary  con- 
siderably. Many  contain  appreciable  amounts  of  alkali  on 
account  of  the  use  of  metallic  sodium  for  removing  the  last 
traces  of  water.  Occasionally  definite  traces  of  acid  are  pres- 
ent, some  of  the  volatile  acids  formed  during  fermentation 
having  distilled  over  with  the  alcohol.  The  following  pro- 
cedures are  sufficient  to  determine  the  suitability  of  a  sample 
of  alcohol.  To  test  for  alkalies,  50  c.c.  are  mixed  with  a  drop 
of  phenolphthalein  and  evaporated  to  dryness  on  a  water- 
bath.  The  residue  should  be  colorless  and  should  remain 
colorless  on  taking  up  in  a  drop  of  water.  To  test  for  acid, 
50  c.c.  are  mixed  with  0.1  c.c.  of  N/100  sodium  hydroxide  and 
evaporated  to  dryness  with  phenolphthalein.  The  residue, 
if  not  red  on  going  to  dryness,  should  become  red  on  adding  a 
drop  of  water.  These  tests  are  moderately  severe  and  many 
grades  of  absolute  alcohol  fail  to  conform  to  them.  The  re- 
action is  much  more  important  than  the  percentage  of  water. 
It  is  usually  comparatively  easy  to  obtain  95  per  cent  alcohol 
free  from  any  alkali.  Preliminary  tests  indicate  that  the  pres- 
ence of  this  5  per  cent  of  water  is  not  disadvantageous. 

This  test  as  employed  in  the  work  on  nephritis  was  as  fol- 
lows :  one  c.c.  of  serum  was  added  drop  by  drop  to  25  c.c.  of 
alcohol  contained  in  a  test  tube  and  the  mixture  was  thor- 
oughly shaken.  The  precipitated  proteins  were  filtered  off 
using  perfectly  dry  apparatus  so  as  to  exclude  all  water  except 
that  which  was  contained  in  the  serum.     Without  washing 


APPENDIX.  TECHNIQUE  OF  METHODS    105 

the  precipitate,  the  filtrate  with  a  few  drops  of  phenolphthal- 
ein  was  evaporated  to  dryness  on  a  water-bath.  With  all  nor- 
mal sera,  the  alcoholic  filtrate  soon  turns  red  and  on  going  to 
dryness  the  residue,  if  kept  hot,  retains  its  red  color  for  several 
hours  (at  least  six  to  eight).  With  an  early  acidosis  (a  deficit 
of  20  to  30  grams  of  bicarbonate)  the  alcoholic  filtrate  must 
become  rather  concentrated  before  the  red  color  appears  and 
on  going  to  dryness  the  red  color  may  disappear  within  a 
few  minutes.  Specimens  were  usually  observed  frequently 
for  fifteen  minutes.  Such  residues,  even  though  the  color 
may  be  very  faint  on  going  to  dryness,  become  distinctly  red 
on  adding  a  drop  of  water.  It  should  be  noted  that  just 
before  going  to  dryness  the  solution  contains  its  highest  pro- 
portion of  water.  With  more  advanced  depletion  of  bicar- 
bonates  (such  as  75  or  100  grams),  no  red  color  appears  at 
any  stage  of  the  evaporation  but  the  residue  becomes  pink 
or  red  on  adding  water.  With  well  marked  acidosis  (150 
grams  deficit  of  bicarbonate)  the  residue  remains  colorless 
even  on  taking  up  in  water.  In  very  extreme  cases  the  whole 
serum  when  diluted  with  water  (9  parts)  and  boiled  fails  to 
react  alkaline  with  phenolphthalein. 

Titration  of  the  residue  with  dilute  sodium  hydroxide 
(N/200),  after  the  evaporation  of  the  alcohol,  was  carried  out 
in  some  instances  but  the  results  were  not  of  especial  impor- 
tance. 

The  principle  of  titration  by  electrometric  methods  is  ex- 
tremely simple.  The  point  of  neutralization  of  an  acid  by  an 
alkali  is  readily  determined  by  conductivity  measurements. 
On  mixing  an  acid  and  an  alkali  the  conductivity  decreases 
as  the  neutral  point  is  approached  reaching  its  minimum  ex- 
actly at  neutrality.  Then  the  addition  of  either  acid  or  base, 
but  especially  of  acid,  causes  the  conductivity  to  increase 
since  the  hydrogen  and  hydroxyl  ions  are  better  conductors 
than  the  neutral  ions. 

The  details  of  this  method  are  fully  described  in  the  litera- 
ture.27-66.   They  will  not  be  repeated  here  primarily  because 


106  THE  PRINCIPLES  OF  ACIDOSIS 

this  determination  is  not  of  clinical  interest  in  the  study  of 
acidosis.  Henderson  and  many  other  workers  have  empha- 
sized that  the  hydrogen  ion  concentration  of  the  blood  does 
not  change  except  as  a  terminal  event.  While  it  was  of  the 
utmost  importance  to  establish  this  fact,  further  confirma- 
tion of  its  seems  superfluous. 

Considerable  importance  has  recently  been  attached  by 
Rowntree  to  a  colorimetric  test  for  studying  the  reaction  of 
the  blood.  Rowntree  and  his  associates  14~67  separated  the 
protein  of  the  blood  by  dialysis  testing  the  dialysate  with 
phenosulphonephthalein,  either  with  or  without  the  addition 
of  dilute  (N/50)  acids  and  alkalies.  The  dialysis  of  blood  and 
blood  serum  obviously  introduces  many  factors  which  would 
alter  the  hydrogen  ion  concerntration.  Rowntree  u  considers 
that  by  a  happy  counterbalancing  of  errors  the  net  result 
approximates  closely  the  original  hydrogen  ion  concentration 
of  the  blood.  Unfortunately  the  hydrogen  ion  concentrations 
which  are  obtained  do  not  support  the  view  of  Henderson 
just  mentioned.  Occasionally  marked  change  is  found  in 
conditions  in  which  the  evidence  of  acidosis  is  not  definite. 
Moreover  in  acidosis,  extreme  values  are  found  such  as  have 
not  been  discovered  by  precise  electrometric  measurements. 
The  authors  also  report  that  normal  values  may  occur  in 
definite  acidosis.  The  method  therefore  loses  considerably 
in  clinical  interest  since  several  reliable  methods  are  available 
for  the  accurate  diagnosis  of  acidosis. 

The  reaction  of  the  dialysate  of  the  serum  is  of  interest 
in  its  bearing  on  the  question  of  what  fractions  of  the  alkaline 
factors  in  the  serum  are  dialy sable.  In  some  early  work 
Brandenburg  68  maintained  that  the  alkaline  content  of  the 
serum  was  divisible  into  two  fractions,  namely,  (1)  the  dif- 
fusible mineral  alkali,  largely  the  carbonates,  a  fraction  that 
is  small  in  amount  and  relatively  constant,  (2)  and  a  second 
fraction  of  alkali  that  is  bound  to  the  protein  and  is  not 
diffusible,  this  being  the  fraction  which  is  responsible  for  the 
variation  in  sera.     In  the  work  with  the  reaction  to  the 


APPENDIX.  TECHNIQUE  OF  METHODS    107 

protcin-frcc  filtrates  to  phenolphthalein,28  the  view  was  ex- 
pressed that  contrary  to  Brandenburg's  position,  the  car- 
bonates constituted  an  important  factor  in  the  alkali  reserve 
of  the  blood  and  that  they  were  subject  to  variation.  The 
work  of  Rowntree  on  the  variation  in  the  reaction  of  the 
protein-free  dialysate  to  phenolphthalein  also  fails  to  support 
Brandenburg's  conclusion. 

For  routine  clinical  purposes  the  determination  of  the  car- 
bon dioxide  content  of  the  alveolar  air  does  not  require  to  be 
supplemented  by  the  same  determination  upon  the  blood. 
Under  special  conditions  and  for  special  purposes,  the  de- 
termination of  the  carbon  dioxide  content  of  the  blood  may 
be  very  valuable.  In  seeking  confirmation  of  the  evidence 
of  acidosis  in  nephritis  I  have  described  an  adaptation  of 
Warburg's  method  for  determining  relatively  small  quanti- 
ties of  carbon  dioxide  and  permitting  the  use  of  moderately 
large  amounts  of  blood.24  This  method  however  was  intended 
only  for  special  investigations  of  unknown  conditions  and 
was  not  adapted  for  routine  work.  A  method  for  clinical 
purposes  has  recently  been  devised  by  Van  Slyke  65  permit- 
ting rapid  and  accurate  determinations  on  small  quantities  of 
blood. 

Determination  of  the  Tolerance  to  Sodium 
Bicarbonate 

This  test  may  be  carried  out  either  by  the  ingestion  or  in- 
travenous injection  of  bicarbonate.  For  the  detection  of  a 
slight  increase  in  tolerance  it  is  quite  sufficient  to  give  5 
grams  of  sodium  bicarbonate  by  mouth  every  2  or  3  hours 
until  the  urine  becomes  neutral  or  alkaline  to  litmus.  The 
bicarbonate  should  be  given  in  a  moderate  amount  of  water 
and  the  patient  should  void  before  each  administration. 
Specimens  of  urine  which  are  not  distinctly  acid  should  be 
boiled  thoroughly  to  convert  bicarbonate  to  carbonate  so 
that  it  will  react  readily  to  litmus.     As  a  control  for  the 


108  THE  PRINCIPLES  OF  ACIDOSIS 

tolerance  tests,  Palmer  and  Henderson  have  recommended 
the  colorimetric  determination  of  the  hydrogen  ion  concen- 
tration of  the  urine  rather  than  the  reaction  to  litmus.  How- 
ever, the  same  conclusions  regarding  the  dosage  which  is 
required  to  change  the  reaction  of  the  urine  can  be  obtained 
much  more  simply  by  the  use  of  litmus  paper. 

Intravenous  injection  may  be  required  if  abnormalities  of 
the  gastrointestinal  tract  exist  and  when  large  doses  of  bi- 
carbonate become  necessary.  Even  in  a  normal  person  with- 
out any  acidosis  as  much  as  3  to  5  grams  of  bicarbonate  can 
be  given  intravenously  without  discomfort  and  of  course 
can  be  repeated  at  intervals  of  2  or  3  hours  until  the  reaction 
of  the  urine  changes.  In  outspoken  acidosis  massive  injec- 
tions of  bicarbonate  are  indicated.  A  very  ordinary  dose  for 
intravenous  injection  would  be  one-half  liter  of  a  4  or  5  per 
cent  solution  repeating  this  dosage  every  4  to  6  hours.  A 
liter  of  5  or  6  per  cent  solution  given  slowly  over  a  period  of 
one-half  to  one  hour  should  be  regarded  as  a  maximal  dose. 
One  must  approach  with  some  caution  the  point  at  which  the 
urine  is  about  to  change  over  to  an  alkaline  reaction.  Exami- 
nation of  the  urine  gives  no  warning  of  this  approaching 
change.  Observations  on  the  reaction  of  the  blood  serum  to 
phenolphthalein  or  determinations  of  the  carbon  dioxide  of 
the  blood  or  alveolar  air  will  give  suitable  evidence.  As  these 
factors  become  nearly  normal,  the  dosage  of  bicarbonate 
should  be  reduced  at  least  to  about  ten  grams.  There  is  often 
some  hesitation  about  giving  large  volumes  of  fluid  intra- 
venously on  account  of  the  possibility  of  dilatation  of  the 
right  side  of  the  heart.  However,  even  with  cardiac  lesions, 
provided  they  are  compensated,  an  injection  of  one-half 
liter  of  solution  can  safely  be  given  intravenously  provided 
it  is  injected  very  slowly  (three  quarters  to  one  hour)  by  the 
gravity  method.  These  figures  apply  only  to  the  "  bicarbon- 
ate "  and  not  to  the  normal  carbonate.  Moreover,  pre- 
cautions must  be  used  in  sterilization  to  prevent  excessive 


APPENDIX.  TECHNIQUE  OF  METHODS    109 

formation  of  the  carbonate.  Even  at  room  temperature  the 
bicarbonate  is  hydrolyzed  according  to  the  equation 

2  Na'HCO's ^ NaNaCO'a  +  HOH'  +  C02, 

the  carbon  dioxide  escaping  from  solution  and  the  normal  car- 
bonate and  water  immediately  hydrolyzing  as  follows : 

NaNaCO'a  +  HOH'  ^  NaOH'  +  NaHC0'3. 

These  reactions  being  reversible,  the  exact  equilibrium  that 
is  established  varies  with  the  proportion  of  these  salts,  the 
dilution  and  the  temperature.  On  boiling  such  a  solution  the 
carbon  dioxide  is  driven  off  very  rapidly  with  conversion  of 
the  bicarbonate  to  normal  carbonate.  On  sterilization  in  the 
autoclave,  less  change  takes  place  since  the  carbon  dioxide 
cannot  excape  from  the  closed  vessel;  it  eventually  comes  into 
equilibrium  with  the  solution  and  prevents  further  change. 
With  a  little  precaution  a  sterile  solution  of  a  five  per  cent 
bicarbonate  can  be  obtained  containing  an  amount  of  normal 
carbonate  so  small  that  at  least  it  is  not  disadvantageous. 
Strong  narrow-mouthed  bottles  are  filled  almost  full  of  bi- 
carbonate solution  so  as  to  reduce  the  air  space  to  a  minimum. 
Tightly  fitting  stoppers  should  be  tied  in  place.  If  there  is 
not  much  leakage,  this  in  itself  will  secure  a  suitable  solu- 
tion composed  largely  of  bicarbonate.  However,  as  an  ad- 
ditional precaution,  these  bottles  can  readily  be  sterilized  in 
an  atmosphere  of  carbon  dioxide.  To  secure  this,  the  auto- 
clave is  raised  to  the  boiling  temperature  and  water  at  the 
boiling  point  is  provided  (either  in  the  bottom  of  the  auto- 
clave or  in  an  open  dish).  The  sealed  bottles  of  bicarbonate 
solution  are  put  in  the  heated  autoclave  and  a  handful  of 
bicarbonate  is  thrown  into  the  hot  water.  The  door  of  the 
autoclave  is  closed  at  once  and  the  carbon  dioxide  allowed  to 
evolve  for  a  moment  displacing  the  air  of  the  autoclave,  pref- 
erably through  a  vent  at  the  top.  Then  the  autoclave,  is 
sealed  and  no  steam  should  be  allowed  to  escape  at  any  time 


110  THE  PRINCIPLES  OF  ACIDOSIS 

in  the  sterilization.  The  autoclave  must  be  cooled  to  room 
temperature  to  permit  re'absorption  of  carbon  dioxide  in  case 
sealing  of  the  bottles  was  imperfect.  Such  solutions,  if  well 
stoppered,  will  keep  for  months.  Some  silica  may  gradually 
scale  off  but  the  sterile  clear  solution  can  usually  be  decanted 
from  this. 

Sterile  bicarbonate  may  also  be  obtained  in  an  entirely 
different  manner.  The  normal  carbonate  or  bicarbonate 
after  sterilization  by  heat  can  be  converted  to  bicarbonate 
by  passing  a  stream  of  carbon  dioxide  through  the  solution 
after  cooling  to  room  temperature. 

It  is  only  on  rare  occasions  that  any  complication  comes  up 
with  regard  to  the  reaction  of  the  urine  to  litmus.  Some 
special  consideration  should  be  given  to  those  cases  where 
there  is  ammoniacal  fermentation  in  the  genito-urinary  tract. 
Even  in  these  patients  the  bicarbonate  tolerance  can  be 
readily  determined  since  the  distinction  between  ammonia 
and  the  fixed  bases  is  readily  made.  The  simple  device  of 
merely  heating  the  litmus  paper  is  often  sufficient.  Red 
litmus  paper  which  has  been  turned  blue  by  ammoniacal  urine 
will  regin  its  red  color  on  drying  and  heating  provided  that 
the  specimen  of  urine  was  originally  acid  before  fermentation; 
otherwise  it  will  remain  blue  on  heating.  This  test,  while  it 
was  found  adequate  in  many  instances,  sometimes  gave  in- 
decisive results,  the  litmus  occasionally  becoming  more  or 
less  discolored  in  heating.  For  these  cases,  the  urine  was 
heated  to  boiling  over  a  free  flame,  maintaining  an  adequate 
volume  of  fluid  by  the  addition  of  water,  until  no  trace  of 
ammonia  was  given  off.  The  urine  then  possesses  the  reaction 
which  it  had  before  fermentation.  This  procedure  may  be 
tested  very  easily  by  taking  a  specimen  of  normal  acid  urine, 
making  it  alkaline  with  ammonia  and  then  boiling.  The  acid 
reaction  will  return  comparatively  soon.  If  fixed  base  is 
added,  such  as  sodium  hydroxide,  the  acid  reaction  cannot 
return  and  moreover  ammonia  will  be  given  off  from  the 
breaking  up  of  the  urea.     Moreover,  if  much  hydroxide  is 


APPENDIX.  TECHNIQUE  OF  METHODS     111 

added,  the  driving  off  of  all  the  ammonia  may  become  a  con- 
siderable undertaking  necessitating  the  breaking  up  of  all  of 
the  urea. 

If  it  is  desired  to  make  elaborate  investigations  of  the  acid- 
ity of  the  urine,  comparatively  simple  methods  are  available 
for  determining  either  the  titration  values  69  or  the  hydrogen 
ion  content  colorimetrically.23  Numerous  studies  of  this  na- 
ture have  not  yet  revealed  any  conditions  in  which  these  data 
are  of  especial  clinical  interest. 


BIBLIOGRAPHY 

1.  Boussingault,  M.    Recherches  sur  la  Quantite  d'Ammoniaque 

Contenue  dans  1'Uriiie.  An.  de  Chimie  et  Physique,  1850, 
3me,  29,  472.  Translated  in  Jour,  fur  Praktische  Chemie, 
1850,  51,  281. 

2.  Folin,  O.     The  Acid  Intoxication  Theory.     Tr.  Assn.  Am. 

Phys.,  1907,  22,  256. 

3.  Hallervorden,  E.     Ueber  Ausscheidung  von  Ammoniak  in 

Urin  bei  pathologischen  Zustanden.  Arch.  f.  exper.  Path.  u. 
Pharmakol.,  1879-80,  12,  237. 

4.  Stadelmann,  E.    Ueber  die  Ursachen  der  Pathologischen  Am- 

moniakausscheidung  beim  Diabetes  mellitus  und  des  Coma 
diabeticum.  Arch.  f.  exper.  Path.  u.  Pharmakol.,  1883,  17, 
419. 

5.  Walter  F.    Untersuchungen  liber  die  Wirkung  der  Sauren  auf 

den  Thierischen  Organismus.  Arch.  f.  exper.  Path.  u. 
Pharmakol.,  1877,  7,  148. 

6.  Kussmatjl,  A.    Zur  Lehre  vom  Diabetes  mellitus.    Deutsch. 

Arch.  f.  klin.  Med.,  1874,  14,  1. 

7.  Henderson,  L.  J.    The  Regulation  of  Neutrality  in  the  Animal 

Body.  Science,  1913  (New  Series),  37,  389.  Ibid.,  Ergeb- 
nisse  der  Physiol.,  1909,  8,  254. 

8.  Jones,  H.  C.     Elements  of  Physical  Chemistry.     1910,  4th 

ed.,  page  439. 

9.  Henderson,  L.  J.    The  Theory  of  Neutrality  Regulation  in  the 

Animal  Organism.     Am.  Jour.  Physiol.,  1908,  21,  427. 

10.  Janney,    N.      Die    Ammoniakausscheidung    im    menschliche 

Harne  bei  Zufuhr  von  Harnstoff  und  Natron.  Ztschr.  f. 
physiol.  Chein.,  1911-12,  76,  99. 

11.  Wilson,  D.  W.,  Stearns,  T.,  Janney,  J.  H.,  Jr.    The  Effect  of 

Acid  Administration  on  Parathyroid  Tetany.  Jour.  Biol. 
Chem.,  1915,  21,  169. 

Wilson,  D.  W.,  Stearns,  T.,  Thurlow,  M.  DeG.  The  Acid- 
Base  Equilibria  in  the  Blood  After  Parathyroidectomy. 
Jour.  Biol.  Chem.,  1915,  23,  89. 

Wilson,  D.  W.,  Stearns,  T.,  Janney,  J.  H.,  Jr.,  The  Excre- 
tion of  Acids  and  Ammonia  after  Parathyroidectomy.  Ibid., 
1915,  23, 123. 

112 


BIBLIOGRAPHY  113 

12.  Benedict,  H.    Der  Hydroxylionengehalt  des  Diabetikerblutes. 

Arcli.  f.  d.  gesam.  Physiol.,  190G,  116,  106. 

13.  Hasselbalch,  K.  A.  and  Gammeltoft,  S.  A.    Die  Neutrali- 

tatsrcgulation  des  graviden  Organismus.    Biochem.  Ztschr., 

1915,  68,  233. 

14.  Rowntree,  L.  G.    The  Diagnosis  and  Treatment  of  Acidosis. 

Tr.  Assn.  Am.  Phys.,  1916,  31,  39. 

15.  Walker,  I.  C.  and  Frotiiingiiam,  C.    A  Comparison,  in  Vari- 

ous Diseases,  of  the  Carbon  dioxide  Tension  in  the  Alveolar 
Air  (Plesch  Method)  with  the  Amount  of  Carbon  dioxide  in 
the  Venous  Blood  (Van  Slyke's  Method).    Arch.  Int.  Med., 

1916,  18,  304. 

16.  Van  Slyke,  D.  D.,  Cullen,  G.  E.,  Stillman,  E.    Changes  in 

Blood  Alkalinity  during  Digestion.  Proc.  Soc.  Exper.  Biol, 
and  Med.,  1915,  12,  184. 

17.  Marriott,  W.  McK.    The  Determination  of  Alveolar  Carbon 

dioxide  Tension  by  a  Simple  Method.  Jour.  Am.  Med. 
Assn.,  1916,  66,  1594. 

18.  Porges,   O.,   Leimdorfer,   A.,   Markovict,   E.     Ueber   die 

Kohlensaurespannung  des  Blutes  in  pathologischen  Zustan- 
den.     Ztschr.  f.  klin.  Med.,  1911,  73,  389. 

19.  Douglas,  C.  G.,  Haldane,  J.  S.,  Henderson,  Y.,  Schneider, 

E.  C.  The  Physiological  Effects  of  Low  Atmospheric  Pres- 
sures as  Observed  on  Pike's  Peak,  Colorado.  (Preliminary 
Communication.)  Proc.  Roy.  Soc.  of  London,  Series  B, 
1912,  85,  65. 

Douglas,  C.  G.,  Haldane,  J.  S.,  Henderson,  Y.,  Schnei- 
der, E.  C.  Physiological  Observations  made  on  Pike's  Peak, 
Colorado.  Philosophical  Transactions  of  the  Royal  Society 
of  London,  Series  B,  1912-13,  203,  185. 

Haldane,  J.  S.  Organism  and  Environment  as  Illustrated  by 
the  Physiology  of  Breathing.     1917. 

20.  Cammidge,  P.  J.    Diabetic  Acidosis.    Am.  Med.,  1916,  22,  363. 

21.  Sellards,  A.  W.    Tolerance  for  Alkalies  in  Asiatic  Cholera. 

Philippine  Jour.  Sc,     Sec.  B,  1910,  5,  363. 

22.  Sellards,  A.  W.    The  Determination  of  the  Equilibrium  in  the 

Human  Body  Between  Acids  and  Bases  with  Especial  Refer- 
ence to  Acidosis  and  Nephropathies.  Bull.  Johns  Hopkins 
Hosp.,  1912,  23,  289. 

23.  Palmer,  W.  W.  and  Henderson,  L.  J.    Clinical  Studies  on  Acid 

Base  Equilibrium  and  the  Nature  of  Acidosis.  Arch.  Int. 
Med.,  1913,  12,  153. 


114  BIBLIOGRAPHY 

24.  Sellards,  A.  W.    The  Essential  Features  of  Acidosis  and  Their 

Occurrence  in  Chronic  Renal  Disease.    Bull.  Johns  Hopkins 
Hosp.,  1914,  25,  141. 

25.  Sellards,  A.  W.    A  Clinical  Method  for  Studying  Titratable 

Alkalinity  of  the  Blood  and  its  Application  to  Acidosis. 
Bull.  Johns  Hopkins  Hosp.  1914,  25,  101. 

26.  Howland,  J.  and  Marriott,  W.  McK.    Acetone  Production 

in  Infancy  and  Childhood.    Am.  Jour.  Dis.  Child.,  1916,  12, 
459. 

27.  Peabody,  F.  W.    Studies  on  Acidosis  and  Dyspnoea  in  Renal 

and  Cardiac  Disease.     Arch.  Int.  Med.,  1914, 14,  236. 

28.  Lewis,  T.,  Ryffel,  J.  H.,  Wolf,  C.  G.  L.,  Cotton,  T.,  Bar- 

croft,  J.  Observations  Relating  to  Dyspnoea  in  Cardiac 
and  Renal  Patients.    Heart,  1913-14,  5, 45. 

29.  Straub,  H.  and  Schlayer.    Die  Uramie  eine  Saurevergiftung  ? 

MUnchen.  med.  Wchnschr.,  1912,  59\  569. 

30.  Porges,  O.  and  Leimdorfer,  A.    Ueber  die  Kohlensaurespan- 

nung  bei  Nierenerkrankungen.  Ztschr.  f.  klin.  Med.,  1913, 
77,  464. 

31.  Straub,  H.    Azidose  des  Blutes  bei  Uramie.    MUnchen.  med. 

Wchnschr.,  1914,  612,  1499. 

32.  von  Jaksch,  R.    Ueber  die  Alkalescenz  des  Blutes  bei  Krank- 

heiten.    Ztschr.  f.  klin.  Med.,  1888,  13,  350. 

33.  Naunyn,  B.    Der  Diabetes  Melitus.    Zweite  Auflage,  Wien, 

1906. 

34.  Emerson,  Charles  P.    Clinical  Diagnosis.    Coma  and  Acido- 

sis.    1906,  page  193. 

35.  Fischer,  Martin  H.    Oedema  and  Nephritis.     1912.     New 

York. 

36.  Howland,  J.  and  Marriott,  W.  McK.    Study  of  Acidosis  Oc- 

curring in  the  Nutritional  Disturbances  of  Infancy.  Am. 
Soc.  Advancement  of  Clinic.  Invest.,  1915,  page  18.  Ibid., 
Acidosis  Occurring  with  Diarrhoea.  Am.  Jour.  Dis.  Child., 
1916,  11,  309.  Ibid.,  A  Discussion  of  Acidosis,  with  Special 
Reference  to  that  Occurring  in  Diseases  of  Children.  Bull. 
Johns  Hopkins  Hosp.,  1916,  27,  63. 

37.  Fridericia,  L.  S.  and  Olsen,  Otto.    Untersuchungen  Uber  die 

Kohlensaurespannung  in  der  Alveolarluft  der  Lungen  bei 
akut  febrilen  Krankheiten.  Deutsch.  Arch.  f.  klin.  Med., 
1912,  107,  236. 

38.  Barcroft,  J.    The  Respiratory  Function  of  the  Blood.    1914, 

page  260. 


BIBLIOGRAPHY  115 

39.  Steenbock,  H.,  Nelson,  V.  E.,  Hart,  E.  B.    Acidosis  in  Om- 

nivora  and  Herbivora  and  its  Relation  to  Protein  Storage. 
Jour.  Biol.  Chem.,  1914,  19,  399. 

40.  Chile,  George  W.    The  Origin  and  Nature  of  the  Emotions. 

Alkalescence,  Acidity,  Anesthesia.  A  Theory  of  Anesthesia. 
1915,  page  227. 

41.  Rogers,  L.  and  Shorten,  A.  J.    The  Alkalinity  of  the  Blood 

in  Kala-Azar  and  Cholera  and  the  Technique  of  its  Estima- 
tion.    Indian  Jour.  Med.  Research,  1915,  2,  867. 

42.  Sellards,  A.  W.  and  Shaklee,  A.  O.     Indications  of  Acid 

Intoxication  in  Asiatic  Cholera.  Philippine  Jour.  Sc,  Sec.  B, 
1911,  6,53. 

43.  McLaughlin,  A.  J.  and  Sellards,  A.  W.      Effect  of  the  Con- 

centration of  Solution  in  the  Treatment  of  Collapse  in  Asiatic 
Cholera.     Philippine  Jour.  Sc,  Sec.  B,  1910,  6,  391. 

44.  Wherry,  W.  B.     Forchheimer's  Therapeusis  of  Internal  Dis- 

eases.    1914,  Vol.  4,  839. 

45.  Busquet,  H.  and  Pachon,  V.    Inhibition  Cardiaque  et  Sels  de 

Sodium  en  Injection  Intravasculaire.  Compt.  rend.  Soc.  de 
biol.,  1909,  66,  127. 

46.  Loeb,  Jacques.    On  the  Production  and  Suppression  of  Mus- 

cular Twitchings  and  Hypersensitiveness  of  the  Skin  by 
Electrolytes.  Chicago  Decennial  Publications,  First  Series, 
1903,  10,  3. 

47.  MacCallum,  W.  G.  and  Voegtlin,  Carl.    On  the  Relation  of 

Tetany  to  the  Parathyroid  Glands  and  to  Calcium  Metab- 
olism.    Jour.  Exper.  Med.,  1909,  11,  118. 
MacCallum,  W.  G.  and  Vogel,  K.  M.    Further  Experimental 

Studies  in  Tetany.     Ibid.,  1913,  18,  618. 
MacCallum,  W.  G.,  Lambert,  R.  A.  and  Vogel,  K.  M.    The 

Removal  of  Calcium  from  the  Blood  by  Dialysis  in  the  Study 

of  Tetany.     Pbid.,  1914,  20,  149. 
Voegtlin,  Carl  and  MacCallum,  W.  G.    On  the  Influence  of 

Various  Salts  Upon  Tetany  Following  Parathyroidectomy. 

Jour.  Pharmacol,  and  Exper.  Therap.,  1910-11,  2,  421. 

48.  Fischer,  Martin  H.    Further  Remarks  on  the  Treatment  of 

Nephritis.     Tr.     Assn.  Am.  Phys.,  1912,  27,  608. 

49.  Edsall,  David  L.     A  Preliminary  Communication  Concern- 

ing the  Nature  and  Treatment  of  Recurrent  Vomiting  in 
Children.    Am.  Jour.  Med.  Sc.  (New  Series),  1903,  125,  629. 

50.  Marriott,  W.  McK.  and  Howland,  J.     Phosphate  Reten- 

tion as  a  Factor  in  the  Production  of  Acidosis  in  Nephritis. 
Arch.  Int.  Med.,  1916,  18,  708. 


116  BIBLIOGRAPHY 

51.  von  Noorden,  Carl  and  Mohr,  L.    The  Acid  Autointoxica- 

tions, 1903.    (a)   Page  78,  (b)  pp.  76  and  77,  (e)   pp.  21  and 
54,  (d)   p.  13. 

52.  Osborne,  T.  B.,  Mendel,  L.  B.,  Ferry,  Edna  L.    Feeding 

Experiments  With  Isolated  Food-Substances.    Carnegie  In- 
stitution of  Washington,  1911,  Pub.  156,  Part  II,  page  80. 

53.  Magnus-Levy,  A.    On  Diabetic  Acidosis.    Bull.  Johns  Hop- 

kins Hosp.,  1911,  22,  46. 

54.  Henderson,  L.  J.  and  Palmer,  W.  W.    On  the  Intensity  of 

Urinary  Acidity  in  Normal  and  Pathological  Conditions. 
Jour.  Biol.  Chem.,  1912-13,  13,  393. 

55.  von   Noorden,  Carl.     Metablism  and  Practical   Medicine. 

Vol.  3,  page  604.     Pathology  of  Metabolism.     1907. 

56.  McCollum,  E.  V.  and  Hoagland,  D.  R.    Studies  of  the  Endog- 

enous Metabolism  of  the  Pig  as  Modified  by  Various  Factors. 
Jour.  Biol.  Chem.,  1913,  16,  299. 

57.  Eppinger,  Hans.    Beitrag  zur  Lehre  von  der  Saurevergiftung. 

Wien.  klin.  Wchnschr.,  1906,  19,  111.  (An  excellent  discus- 
sion of  ammonia  excretion  in  herbivora  and  carnivora.) 

58.  Folin,  Otto.     Eine  neue  Methode  zur  Bestimmung  des  Am- 

moniaks  im  Harn  und  andern  thierischen  Fliissigkeiten. 
Ztschr.  f.  physiol.  Chem.,  1902-03,  37,  161.  Ibid.  Note  on 
the  determination  of  ammonia  in  urine.  Jour.  Biol.  Chem., 
1910-11,  8,  497. 
Folin,  O.  and  Macallum,  A.B.  On  the  determination  of 
ammonia  in  urine.     Jour.  Biol.  Chem.,  1912-13,  11,  523. 

59.  Shaffer,  P.  A.    A  Method  for  the  Quantitative  Determination 

of  /3-Oxybutyric  Acid  in  Urine.    Jour.  Biol.  Chem.,  1908-09, 
5,  211. 
Shaffer,  P.  A.  and  Marriott,  W.  McK.    The  Determination 
of  Oxybutyric  Acid.    Jour.  Biol.  Chem.,  1913-14,  16,  265. 

60.  Marriott,  W.  McK.    The  Determination  of  Acetone.    Jour. 

Biol.  Chem.,  1913-14, 16,  281;  Nephelometric  Determination 
of  Minute  Quantities  of  Acetone,  Ibid.,  1913-14,  16,  289; 
The  Determination  of  /3-Oxybutyric  Acid  in  Blood  and  Tis- 
sues Ibid.,  1913-14,  16,  293. 

61.  Boothby,  W.  M.  and  Peabody,  F.  W.     A  Comparison  of 

Methods  of  Obtaining  Alveolar  Air.  Arch.  Int.  Med.,  1914, 
13,  497. 

62.  Fridericia,  L.  S.    En  klinisk  Metode  til  Bestemmelse  af  Kul- 

syrespaendingen  i  Lungeluften.  Hospital  Stidende,  1914, 
57,  585. 


BIBLIOGRAPHY  117 

62a.    Poulton,  E.  P.    The  Significance  of  Alveolar  Carbon  Dioxide 
Determinations  in  the  Treatment  and  Prognosis  of  Diabetes. 
British  Medical  Jour.,  1915,  2,  393. 

63.  Howland,  J.  and  Marriott,  W.  McK.     Acidosis  Occurring 

with  Diarrhoea.     Am.  Jour.  Dis.  Child.,  1916,  11,  309. 

64.  Haldane,  J.  S.    Methods  of  Air  Analysis.     1912. 

65.  Van  Slyke,  D.  D.     Communication  to  appear  in  the  June 

number  of  the  Jour.  Biol.  Chem.,  1917,  vol.  30. 

66.  Sorensen,  S.  P.  L.     Ueber  die  Messung  und  Bedeutung  der 

Wasserstoffionenkonzentration    bei   biologischen   Prozessen. 

Ergebnisse  d.  Physiol.,  1912,  12,  393. 
Hasselbalch,  K.  A.    Elektrometrische  Reaktionsbestimmung 

kohlensaurehaltiger  FlUssigkeiten.     Biochem.  Ztschr.,  1911, 

30,  317. 
Hasselbalch,   K.   A.   and   Lundsgaard,   Chr.     Electrome- 

trische   Reaktionsbestimmung   des   Blutes   bei   Korpertem- 

peratur.     Biochem.  Ztschr.,  1912,  38,  77. 
Michaelis,   Leonor  and   Rona,   Peter.     Electrochemische 

Alkalinitatsmessungen  an  Blut  und  Serum.  Biochem.  Ztschr., 

1909,  18,  317. 
66a.   Michaelis,  L.    Die  Wasserstoffionenkonzentration,  ihre  Be- 
deutung fur  die  Biologie  und  die  Methoden  ihre  Messung. 

Berlin,  1914. 

67.  Levy,  R.  L.,  Rowntree,  L.  G.,  Marriott,  W.  McK.     A 

Simple  Method  for  Determining  Variations  in  the  Hydrogen- 
Ion  Concentration  of  the  Blood.    Arch.  Int.  Med.,  1915,  16, 
389. 
Levy,  R.  L.  and  Rowntree,  L.  G.     A  Study  of  the  Buffer 
Value  of  the  Blood.     Arch.  Int.  Med.,  1916,  17,  525. 

68.  Brandenburg,  F.     Cited  by  Emerson,  Charles  P.,  Clinical 

Diagnosis.     1913,  4th  ed.,  page  569. 

69.  Folin,  Otto.    The  Acidity  of  Urine.    Am.  Jour.  Physiol.,  1903, 

9,  265. 

70.  Peters,  J.  P.,  Jr.     Carbon  dioxide  Acidosis:    The  Cause  of 

Cardiac  Dyspnoea.     Am.  Jour.  Physiol.,  1917,  43,  113. 

71.  Joslin,  E.  P.    The  Treatment  of  Diabetes  Mellitus.     1916, 

page  295. 


INDEX  OF  AUTHORS 


Barcroft,  J.,  40,  50. 

Benedict,  H.,  18. 

Boothby,  W.  M.,  96,  98. 

Boussingault,  M.,  3. 

Brandenburg,  F.,  106. 

Busquet,  H.,  59. 

Cammidge,  P.  J.,  22. 

Cotton,  T.,  40. 

Crile,  G.  W.,  51. 

Cullen,  G.  E.,  21. 

Edsall,  D.  L.,  67. 

Emerson,  C.  P.,  42. 

Eppinger,  H.,  116. 

Ferry,  E.  L.,  68,  81. 

Fischer,  M.  H.,  44,  62,  63,  65,  80. 

Folin,  O.,  3,  18,  95. 

Fridericia,  L.  S.,  49,  96. 

Frothingham,  C,  20,  49. 

Gammeltoft,  S.  A.,  19. 

Haldane,  J.  S.,  96. 

Hallervorden,  E.,  3. 

Hart,  E.  B.,  51. 

Hasselbalch,  K.  A.,  19. 

Henderson,  L.  J.,  9,  10,  13,  26,  33, 

74,  84,  108. 
Hoagland,  D.  R.,  80. 
Howland,  J.,  35,  48,  66,  67,  75,  99. 
Janney,  N.,  112. 
Jones,  H.  C,  112. 
Joslin,  E.  P.,  66. 
Kussmaul,  A.,  3. 
Leimdorfer,  A.,  21,  40,  52. 
Lewis,  T.,  40. 
Loeb,  J.,  59. 
MacCallum,  W.  G.,  59. 
McCoUum,  E.  V.,  80. 
McLaughlin,  A.  J.,  58. 
Magnus-Levy,  A.,  73. 


Markovici,  E.,  21,  52. 

Marriott,  W.  McK.,  21,  35,  48,  66,  67, 

75,  95,  99,  100. 
Mendel,  L.  B.,  68,  81. 
Michaelis,  L.,  19. 
Naunyn,  B.,  42. 
Nelson,  V.  E.,  51. 
Olsen,  O.,  49. 
Osborne,  T.  B.,  68,  81. 
Pachon,  V.,  59. 

Palmer,  W.  W.,  26,  33,  74,  108. 
Peabody,   F.  W.,  19,  39,  68,  72,  74, 

96,  98. 
Peters,  J.  P.,  Jr.,  52. 
Porges,  O.,  21,  40,  52. 
Poulton,  E.  P.,  96. 
Rogers,  L.,  57. 
Rowntree,  L.  G.,  20,  33,  106. 
Ryffel,  J.  H.,  40. 
Schlayer,  40. 

Sellards,  A.  W.,  113.  114,  115. 
Shaffer,  P.  A.,  95. 
Shaklee,  A.  O.,  58. 
Shorten,  A.  J.,  57. 
Sorensen,  S.  P.  L.,  117. 
Stadelmann,  E.,  3. 
Steenbock,  H.,  51. 
Stillman,  E.,  21. 
Straub,  H.,  40. 
Van  Slyke,  D.  D.,  20. 
von  Jaksch,  R.,  41. 
von  Noorden,  C.,  48,  53,  68. 
Walker,  I.  C.,  20,  49. 
Walter,  F.,  3. 
Wherry,  W.  B.,  59. 
Wilson,  D.  W.,  14. 
Wolf,  C.  G.  L.,  40. 


118 


INDEX  OF  SUBJECTS 


Acetone 

acidosis  persisting  after  disappear- 
ance of,  35. 

determination  of,  95. 

interpretation  of,  35. 

occurrence  of,  77. 
"  Acetone  bodies,"  variability  of,  in 

acidosis,  77. 
"  Acidaemia,"  43. 
Acidosis 

choice  of  tests  for,  38. 

clinical  signs  of,  17. 

compensated  and  uncompensated, 
43. 

definition  of,  47. 

early  observations,  3. 

etiology,  73. 

experimental  production  of,  3,  67. 

fundamental    and   incidental    fea- 
tures of,  76. 

laboratory  methods  for  detection 
of,  17. 

occurrence  of,  48. 

proof  of,  in  early  nephritis,  39. 

"  relative  "  and  "  absolute,"  43. 

relative  value  of  various  tests  for, 
34. 

therapy  of,  53. 
Acids,  excess  of,  in  normal  diet,  9. 
Air  hunger 

explanation  of,  13. 

noted  by  Kussmaul,  3. 

symptom  of  acidosis,  17. 
Alkalies 
.     choice  of,  for  therapy,  65. 

depletion  of,  in  nephritis,  63. 

essential  to  life,  4. 

precautions  in  use  of,  65. 


preparation  of,  for  injection,  108. 
symptoms  following  depletion  of, 

62. 
treatment  by,  see  therapy. 
Alkalinity,  titratable,  see  Titratable 

alkalinity. 
Alkali  starvation,  42. 
Alkalosis,  14,  84. 

lack  of  evidence  for,  15,  16. 
Alveolar  air 
carbon  dioxide  of,  17. 
determination  of  carbon  dioxide  in, 

95. 
interpretation  of  carbon  dioxide  of, 

21. 
lowering    in   nephritis    of    carbon 
dioxide  of,  40. 
Ammonia 

discovery  of  pathological  amounts 

of,  3. 
effect  of  alkali  therapy  on,  78. 
increase  of,  in  primary  disturbances 

of  protein  metabolism,  23. 
normal    amounts    of,    in    certain 

forms  of  acidosis,  23,  75,  77. 
physiological     occurrence     of,     in 

urine,  10. 
relationship  to  other  tests  for  aci- 
dosis, 37. 
Asiatic  cholera 
tolerance  of  patients  to  bicarbon- 
ate, 25. 
treatment  of  acidosis  in,  54 
Association,  5. 
/3-oxybutyric  acid 

discovery  of  in  urine,  3. 

determination  of,  95. 

See  also  "  Acetone  bodies." 


119 


120 


INDEX  OF  SUBJECTS 


Bicarbonate 

determination  of  tolerance  to,  107. 

execretion  of,  in  health,  24. 

storage  of,  in  acidosis,  25. 

sterilization  of,  108. 
Blood 

carbon  dioxide  of,  17. 

carbon  dioxide  of,  in  uraemia,  32. 

composition  maintained  at  expense 
of  other  tissues,  46,  88. 

determination  of  carbon  dioxide  of, 
32,  107. 

determination   of   titratable   alka- 
linity of,  103. 

physicochemial  reaction  of,  18. 

reaction  in  pregnancy,  19. 
Calcium,  22,  24,  67,  68,  82. 
Carbon  dioxide 

determination  of,  in  blood,  107. 

determination  of,  in  alveolar  air, 
95. 

interdependency  of,  in  blood  and 
alveolar  air,  20. 

lowering  of,  in  cardiac  cases,  21. 

lowering  of,  at  high  altitudes,  21. 

lowering  of,  in  uraemia,  32. 

relationship  to  other  tests  for  aci- 
dosis, 35. 
Cirrhosis  of  liver,  acidosis  in,  49. 
Comas 

differentiation  of,  70. 

from  lack  of  salts,  68. 
Compensatory  processes,  12. 
Definition  of  acidosis,  47,  83. 
Diabetes,  use  of  alkalies  in,  66,  89. 
Diagnosis  of  acidosis,  17. 
Diet,  excess  of  acids  in  normal,  9. 
Differentiation  of  comas,  69. 
Equilibrium  between  acids  and  bases, 
4. 

Henderson's  factor,  9. 

mechanism  of,  in  health,  11. 

mechanism  of,  in  disease,  12,  84. 


Etiology 

defective  oxidation  in  diabetes,  73. 

defective  elimination  in  nephritis, 
73,  74,  75. 
Exaggeration  of  frequency  of  acido- 
sis, 51. 
Excretion,  faulty,  as  cause  of  acido- 
sis, 74. 
Experimental  acidosis,   3,  67. 
Fixed   bases,   necessary  for   internal 

respiration,  13. 
"  Food-intoxications,"  acidosis  in.  48. 
Fundamental  features  of  acidosis,  76, 

85. 
Hepatic  cirrhosis,  acidosis  in,  49. 
Historical  note,  3. 
Hydrogen  ion  concentration,  7. 

constancy  of,  84. 

maximal  change  of,  in  acidosis,  19. 
Hydroxyl  ion  concentration,  7. 
Indicators,  6. 
Internal    Respiration,   role   of   fixed 

bases,  13. 
Interpretation  of 

acetone,  35. 

ammonia,  37. 

carbon  dioxide,  21. 

tolerance  to  bicarbonate,  26,  33. 
Laboratory  tests  for  acidosis,  17 

effect  of  therapy  on,  64. 
Law  regarding  composition  of  blood 

in  disease,  46,  88. 
Magnesium,  22,  24,  68. 
Nephritis 

acidosis  in  earlier  stages,  39. 

as  a  cause  of  acidosis,  80. 

carbon  dioxide  of  alveolar  air  in,  40. 

explanation  of  acidosis  in,  74. 

in  Asiatic  cholera,  25. 

treatment  of  acidosis  in,  60. 
Neutrality  Regulation.    See  equilib- 
rium between  acids  and  bases 
Occurrence  of  acidosis,  48. 


INDEX   OF  SUBJECTS 


121 


Oedema,  63. 
Parathyroid  tetany,  14. 
Phosphates 

increased  in  acidosis,  75. 

in  neutrality  regulation,  9. 

Physicochemical  reaction,  6. 
of  blood  in  acidosis,  18. 
principle  of  method  for  determin- 
ing, 105. 
Pregnancy,  reaction  of  blood  in  19. 
Qualitative  changes,   absence  of,   in 
compensation  against  acidosis,  83. 
Quantitative  changes  of  normal  com- 
pensatory processes,  12. 

Reaction 

"  titratable,"  5. 
physicochemical,  6. 
to  indicators,  6. 
and  titration  values,  7. 

Relationship  of  various  tests  for  aci 
dosis,  34. 

Resume,  81. 

Sterilization  of  Bicarbonate,  108. 

Symptoms  of  acidosis,  17. 

effect  of  alkali  therapy  on,  55,  60, 
67. 

of  depletion  of  alkali,  61,  87. 
Tables 

effect  of  treatment  on  titratable  al- 
kalinity, 31. 

fundamental  and  variable  features 
of  acidosis,  77. 

physicochemical  reaction  and  titra- 
tion values,  7. 


Therapy  of  Acidosis 

choice  of  alkali  for,  65. 

effect  of,  on  laboratory  tests,  64. 

in  Asiatic  Cholera,  54. 

in  food  "  intoxications,"  66. 

in  nephritis,  60. 

sterilization  of  bicarbonate  for,  108. 

theory  of,  53. 
Titratable  alkalinity  of  blood 

determination  of,  103. 

relationship  to  other  tests  for  acido- 
sis, 36. 
Titratable  reaction,  5,  6. 
Tolerance  to  bicarbonate 

delicacy  of,  as  test  for  acidosis,  25. 

determination  of,  107. 

in  Asiatic  cholera,  25. 

in  nephropathies,  26. 

in  uraemia,  31. 

interpretation  of,  26,  33. 

terminology,  33. 

relationship  to  other  tests  for  acido- 
sis, 37. 

relationship  to  clinical  symptoms, 
61. 

relationship     to      phenolsulphone- 
phthalein  tests,  69. 
Uraemia 

carbon  dioxide  of  blood  in,  28. 

titratable  alkalinity  of  blood  in,  31. 
Urine 

original   reaction   of    ammoniacal, 
110. 

total  acidity,  22. 
Value  relative    of  various    tests  for 
acidosis,  34. 


PBINTED  AT 

THE  HARVARD  UNIVEBSITY  PBES9 

CAMBRIDGE,  MASS.,  U.  S.  A. 


UC  SOUTHERN  REGIONAL  LIBRARY  FACILITY 


AA      000  221  325    4 


